Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRASG12C Inhibitor Efficacy
Open accessPublished version of a preprint
Abstract
Non–small lung cancers (NSCLC) frequently (∼30%) harbor KRAS driver mutations, half of which are KRASG12C. KRAS-mutant NSCLC with comutated STK11 and/or KEAP1 is particularly refractory to conventional, targeted, and immune therapy. Development of KRASG12C inhibitors (G12Ci) provided a major therapeutic advance, but resistance still limits their efficacy. To identify genes whose deletion augments efficacy of the G12Cis adagrasib (MRTX-849) or adagrasib plus TNO155 (SHP2i), we performed genome-wide CRISPR/Cas9 screens on KRAS/STK11-mutant NSCLC lines. Recurrent, potentially targetable, synthetic lethal (SL) genes were identified, including serine–threonine kinases, tRNA-modifying and proteoglycan synthesis enzymes, and YAP/TAZ/TEAD pathway components. Several SL genes were confirmed by siRNA/shRNA experiments, and the YAP/TAZ/TEAD pathway was extensively validated in vitro and in mice. Mechanistic studies showed that G12Ci treatment induced gene expression of RHO paralogs and activators, increased RHOA activation, and evoked ROCK-dependent nuclear translocation of YAP. Mice and patients with acquired G12Ci- or G12Ci/SHP2i-resistant tumors showed strong overlap with SL pathways, arguing for the relevance of the screen results. These findings provide a landscape of potential targets for future combination strategies, some of which can be tested rapidly in the clinic. Significance: Identification of synthetic lethal genes with KRASG12C using genome-wide CRISPR/Cas9 screening and credentialing of the ability of TEAD inhibition to enhance KRASG12C efficacy provides a roadmap for combination strategies. See related commentary by Johnson and Haigis, p. 4005
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- Findingown data
RNA-seq of MRTX-849-treated H2030 and H2122 cells separated control and treated groups by unsupervised clustering.
“Unsupervised clustering clearly separated control and treated groups in both lines”
Quote in the paperNot a substantial claim - Findingown data
Similar increases in nuclear YAP were observed in H2122, H23, and MiaPaca2 cells.
“Similar results were obtained with other NSCLC lines (H2122, H23) and with the PDAC cell line MiaPaca2”
Quote in the paperNot a substantial claim - Findingown data
Genome-wide CRISPR/Cas9 screens identified genes whose inactivation enhances MRTX-849 efficacy alone or with TNO-155 in four KRAS G12C-mutant NSCLC cell lines.
“we used genomewide CRISPR/Cas9 screening to identify genes whose inactivation enhances the efficacy of MRTX-849 alone or in combination with TNO-155 in four KRAS G12C -mutant NSCLC cell lines.”
Quote in the paperSubstantial claim- Rests on an assumption: The four KRAS G12C-mutant NSCLC cell lines with STK11 and KEAP1 co-mutations are representative of KRAS G12C-mutant NSCLC with these co-mutations.
- Rests on an assumption: CRISPR/Cas9 dropout under drug treatment in these cell lines identifies genes whose inactivation enhances drug efficacy.
- Findingown data
In H2030 cells, TEAD reporter activity increased more than sixfold after MRTX-849 treatment at IC50 for 48 hours.
“TEAD reporter activity increased by >6-fold in G12Ci-treated cells (Fig. 3A).”
Quote in the paperSubstantial claim - Findingown data
MRTX-849 treatment increased nuclear YAP in H2030 cells starting at 4 hours and peaking at 24-48 hours.
“MRTX-849 treatment also increased levels of nuclear YAP in H2030 cells, beginning at 4 hours and peaking at 24-48 hours”
Quote in the paperSubstantial claim
- Findingown data
CYR61 transcript levels increased after 48 hours of MRTX-849 treatment in two NSCLC lines.
“transcript levels of the YAP/TEAD-inducible gene CYR61 were increased after 48h of MRTX-849 treatment in two NSCLC lines tested”
Quote in the paperSubstantial claim - Findingown data
SHOC2 was depleted in three of four cell lines.
“SHOC2, a known SL gene in MEK-inhibitor treated cells (32), was depleted in 3/4 lines”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [32] Sulahian, 2019, Synthetic lethal interaction of SHOC2 depletion with MEK inhibition in RAS-driven cancers, Cell Rep source
Not checked in the free run.
- Findingown data
Many upregulated pathways after MRTX-849, including Hippo signaling, matched synthetic lethal pathways from the screen.
“Remarkably, many upregulated pathways, including Hippo Signaling, conformed to the SL pathways identified by our screen (compare Fig. 1E and 3C).”
Quote in the paperSubstantial claim - Findingown data
Depletion of TEAD1 or WWTR1 by siRNAs or doxycycline-inducible shRNAs enhanced MRTX-849 efficacy in multiple cell lines.
“TEAD1 or WWTR1 depletion by siRNAs (“Smartpool”) or doxycycline-inducible shRNAs enhanced MRTX-849 efficacy in multiple lines”
Quote in the paperSubstantial claim - Findingcitation
Expression of a dominant negative TEAD1 mutant had similar enhancing effects.
“Expressing a dominant negative TEAD1 mutant (37) had similar effects”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [37] Yuan, 2020, YAP1/TAZ-TEAD transcriptional networks maintain skin homeostasis by regulating cell proliferation and limiting KLF4 activity, Nat Commun source
Not checked in the free run.
- Findingown data
YAP S94A, which cannot associate with TEAD family members, did not affect MRTX-849 response.
“By contrast, YAP S94A , which encodes a mutant unable to associate with TEAD family members (39), did not affect MRTX-849 response”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [39] Zhao, 2008, TEAD mediates YAP-dependent gene induction and growth control, Genes Dev source
Not checked in the free run.
- Findingown data
Knockdown of ELP3 or ELP5 augmented the response to MRTX-849.
“Likewise, knockdown of ELP3 and ELP5 (Fig. 7D-E, Supplementary Fig. S7C-D), which encode components of the elongator complex (52), augmented MRTX-849 response.”
Quote in the paperSubstantial claim - Findingown data
RHO activity increased following MRTX-849 treatment.
“RHO activity (assessed by G-LISA) increased following MRTX-849 treatment (Fig. 3F)”
Quote in the paperSubstantial claim - Findingcitation
VT106, an inactive analog of VT-104 that does not block YAP/TEAD interaction, had no effect on drug sensitivity.
“Furthermore, VT106, an inactive analog of VT-104 that does not block YAP/TEAD interaction (49), had no effect on drug sensitivity.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [49] Tang, 2021, Small molecule inhibitors of TEAD auto-palmitoylation selectively inhibit proliferation and tumor growth of NF2-deficient mesothelioma, Mol Cancer Ther source
Not checked in the free run.
- Findingown data
Knockdown of RIOK2 or VRK1 with siRNAs/shRNAs sensitized several NSCLC cell lines to MRTX-849 at its IC50.
“Reassuringly, siRNAs/shRNAs against RIOK2 (Fig. 7A, Supplementary Fig. S7A) or VRK1 (Fig. 7B, Supplementary Fig. S7B), which encode serine/threonine kinases, sensitized multiple NSCLC lines to MRTX-849 (at its IC50).”
Quote in the paperSubstantial claim - Findingown data
Both MYF-03-69 and VT-104 synergistically augmented MRTX-849 action in multiple NSCLC lines, including lines not mutant for STK11 and/or KEAP1.
“both agents synergistically augmented MRTX-849 action in multiple NSCLC lines, including those that were not STK11 and/or KEAP1 mutant”
Quote in the paperSubstantial claim - Findingown data
Genes annotated as Signaling by RHO GTPases were enriched in the synthetic lethal screens.
“genes annotated as “Signaling by RHO GTPases” were enriched in the SL screens (Fig. 1E)”
Quote in the paperSubstantial claim - Findingown data
More than half of H2030 and H2122 cells show at least some nuclear localization of YAP.
“>50% of H2030 and 2122 cells show at least some nuclear localization of YAP (Fig. 3G-H, Supplementary Fig. S3C-D).”
Quote in the paperNot a substantial claim - Findingown data
Both the G12C inhibitor and the G12C inhibitor plus SHP2 inhibitor screens identified the YAP/TAZ/TEAD pathway as a route to resistance in vitro and in vivo.
“Our G12Ci and G12Ci/SHP2i combination screens both identified the YAP/TAZ/TEAD pathway as a route to resistance in vitro and in vivo.”
Quote in the paperSubstantial claim - Findingown data
The screens identified recurrent synthetic lethal genes with G12C inhibitors across several functional classes, including Hippo and RHO signaling, tRNA processing, heparan sulfate biosynthesis, and novel kinases.
“We identified recurrent synthetic lethal (SL) genes with G12Cis that span a range of functional classes, including genes in pathways related to Hippo and RHO signaling, tRNA processing, and heparan sulfate biosynthesis, as well as several novel kinases.”
Quote in the paperSubstantial claim - Findingown data
RNA-seq of MRTX-849-resistant mouse nodules revealed enriched pathways also enriched in CRISPR screens, including Fanconi anemia, MYC, E2F target, and glycosylation genes.
“RNA-seq revealed multiple enriched pathways (p < 0.05) that were also enriched in the CRISPR/Cas9 screens, including Fanconi anemia, MYC, E2F target, and glycosylation genes”
Quote in the paperSubstantial claim - Findingown data
TEAD1 and TEAD4 were validated as synthetic lethal with MRTX-849/TNO155 using si- and shRNAs and dominant negative TEAD.
“We therefore validated TEAD1 and TEAD4 as SL with MRTX-849/TNO155 using si-and shRNAs and dominant negative TEAD via studies analogous to those used for MRTX-849 alone”
Quote in the paperSubstantial claim - Findingown data
Y27632 increased MRTX-849 efficacy in two cell lines.
“Y27632 addition also increased MRTX-849 efficacy in two cell lines tested”
Quote in the paperSubstantial claim - Findingown data
VT104 at 10 mg/kg/d had minimal single-agent efficacy in either model.
“VT104 (10 mg/kg/d) has minimal single agent efficacy in either model.”
Quote in the paperSubstantial claim - Findingown data
YAP/TAZ pathway signature genes were markedly enriched in MRTX-849-resistant nodules.
“Importantly, YAP/TAZ pathway signature genes (50) were markedly enriched in resistant nodules”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [50] Cordenonsi, 2011, The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells, Cell source
Not checked in the free run.
- Findingown data
The ROCK inhibitor Y27632 inhibited YAP nuclear translocation induced by MRTX-849 at 24 hours and more at 48 hours.
“the ROCK inhibitor Y27632 inhibited YAP nuclear translocation induced by MRTX-849 treatment for 24hr (Supplementary Fig. 3B) and to an even greater extent after 48h of treatment (Fig. 3G-H, quantified in Supplementary Fig. 3C-D).”
Quote in the paperSubstantial claim - Findingown data
FEMRT2, LIMK2, MYLK, and multiple myosin genes were induced in both MRTX-849-treated cell lines.
“FEMRT2, encoding KINDLIN-2, which mediates integrin activation, was also induced in both lines (Supplementary Table S3, Tab 4-5, colored blue), as were LIMK2, which regulates COFILIN and promotes F-actin formation, MYLK, encoding myosin light chain kinase, a which regulates actomyosin contractility (Supplementary Table S3, Tab 4-5, colored orange) and multiple myosin genes”
Quote in the paperSubstantial claim - Findingown data
Combining MRTX849 and VT104 significantly delayed tumor recurrence in both the KCL syngeneic and H2030 xenograft models.
“However, combining MRTX849 and VT104 results in a significant delay in tumor recurrence in both models”
Quote in the paperSubstantial claim - Findingown data
RNA-seq of combo-resistant nodules revealed pathways common to CRISPR synthetic lethal genes, including YAP and WWTR1-stimulated genes, RHO activity regulation, and O-linked glycosylation.
“RNA-seq of nodules from these tumors also revealed pathways common to the CRISPR/Cas9 SL genes (Fig. 6D, colored in red).For example, genes annotated as YAP and WWTR1-stimulated were induced, as were those associated with regulation of RHO activity and O-linked glycosylation”
Quote in the paperSubstantial claim - Findingown data
CRISPR/Cas9 screens on combination-treated H2122, H2030, and H23 cells identified multiple shared and unique synthetic lethal hits.
“Again, screen quality was high (Supplementary Fig. 4C), and multiple shared and unique SL “hits” were identified (Fig. 4A-C).”
Quote in the paperSubstantial claim - Findingown data
The tool VRK1 inhibitor VRK-IN-1 enhanced G12C inhibitor efficacy.
“VRK-IN-1(51), a tool VRK1 inhibitor, also enhanced G12Ci efficacy (Fig. 7C).”
Quote in the paperSubstantial claim - Findingown data
scRNA-seq of two KRAS G12C NSCLC patient tumors resistant to sotorasib or MRTX-849+TNO-155 showed enrichment of resistance pathways suggested by the CRISPR screens and resistant GEMMs.
“Remarkably, resistance pathways suggested by our CRISPR/ Cas9 SL screens and the resistant GEMMs also were enriched in these patient samples.”
Quote in the paperSubstantial claim- Rests on an assumption: Enriched pathways in resistant mouse and patient tumors indicate resistance mechanisms relevant to human KRAS G12C NSCLC.
- Findingown data
The MRTX-849 plus TEAD inhibitor combination was active in select PDAC and CRC cell lines.
“This combination was also active in select PDAC and CRC cell lines”
Quote in the paperNot a substantial claim - Findingown data
Other pathways including EMT, Krebs cycle, DNA damage, KEAP1-NFE2L2, and autophagy were enriched in the human resistant samples.
“Other pathways, including genes associated with epithelial-mesenchymal transition (EMT), Krebs cycle, DNA damage, KEAP1-NFE2L2 pathways, and autophagy, also were enriched in the human samples.”
Quote in the paperSubstantial claim - Findingown data
VT-104 increased the efficacy of MRTX849/TNO-155 combination in NSCLC lines compared with single-agent or two-drug combinations at reduced doses.
“VT-104 also increased the efficacy of combination MRTX849/TNO-155 in NSCLC lines (Supplementary Fig. 5C) compared with single agent therapy or two drug-combinations (all at reduced doses).”
Quote in the paperSubstantial claim - Findingown data
TAZ and TEAD were induced in RPPAs from MRTX-849-resistant tumors.
“In line with these findings TAZ and TEAD were induced in RPPAs from MRTX-849-resistant tumors”
Quote in the paperSubstantial claim - Findingown data
Doxycycline-inducible shRNAs against these genes produced similar sensitization results.
“Similar results were obtained using doxycline-inducible shRNAs (Fig. 7G-I, Supplementary Fig. S7E-G).”
Quote in the paperNot a substantial claim - Findingreasoning
Most of the shared synthetic lethal genes were not detected in the earlier studies.
“Overall, however, the majority of our shared SL genes escaped detection in the prior studies”
Quote in the paperNot a substantial claim - Findingown data
The YAP/TAZ/TEAD pathway is activated in mouse and human models of resistance to G12C inhibitors and to G12C plus SHP2 inhibitors.
“Importantly, we also find evidence that this pathway is activated in mouse and human models of G12Ci and G12Ci +SHP2i-resistance.”
Quote in the paperSubstantial claim - Findingown data
G12C inhibitor treatment induces YAP nuclear translocation and activity.
“We observed that YAP nuclear translocation and activity are induced by G12Ci treatment.”
Quote in the paperSubstantial claim - Findingown data
Combination therapy induced YAP nuclear translocation.
“We also observed that combination therapy induced YAP nuclear translocation, consistent with a shared mechanism”
Quote in the paperSubstantial claim - Findingown data
Several of these genes showed increased expression after adagrasib treatment of lung cancer cell lines.
“Several of these genes also showed increased expression infollowing adagrasib treatment of lung cancer cell lines (Fig. 1E, 3C, 4B, and Supplementary Table 3).”
Quote in the paperNot a substantial claim - Findingown data
MRTX-849 treatment increases RHOA activity.
“MRTX-849 treatment causes increased RHOA activity.”
Quote in the paperSubstantial claim - Findingown data
ROCK inhibitor treatment appeared to block YAP translocation only partially.
“we note ROCK inhibitor treatment appeared to block YAP translocation only partially (Fig. 3G-H, Supplementary Fig. S3C-D).”
Quote in the paperNot a substantial claim - Findingown data
MRTX-849 treatment induces transcription of genes encoding multiple RHO paralogs and GEFs, as well as RHO targets, actin regulators, and myosins including myosin-II.
“we find that MRTX-849 treatment induces the transcription of genes encoding multiple RHO paralogs and GEFs, as well as RHO targets, actin regulators, and myosins (including myosin-II).”
Quote in the paperSubstantial claim - Findingown data
Glycolytic pathway genes were induced in the study's G12C inhibitor-resistant samples.
“glycolytic pathway genes were also induced in our G12Ci-resistant samples (Fig. 6G).”
Quote in the paperNot a substantial claim - Findingown data
Several genes encoding glycolytic enzymes were hits in the screens.
“several genes encoding glycolytic enzymes were hits in our screens.”
Quote in the paperNot a substantial claim - Findingown data
PKN is a synthetic lethal target in the MRTX-849 screen.
“it is also a SL target in our MTRX-849 screen.”
Quote in the paperNot a substantial claim - Findingown data
MRAS RNA increases in H2030 and H2122 cells treated with adagrasib.
“we also observed increases in MRAS RNA in adagrasib-treated H2030 and H2122 cells.”
Quote in the paperNot a substantial claim - Findingown data
Y27632 enhances the effects of MRTX-849.
“our finding that Y27632 enhances the effects of MRTX-849”
Quote in the paperSubstantial claim - Findingown data
Several of these genes showed increased expression in G12C inhibitor-resistant samples.
“Several of these genes also showed increased expression in G12Ci-resistant samples (6B, 6F-G).”
Quote in the paperNot a substantial claim - Premisecitation
In KRAS-mutant NSCLC, co-mutation of STK11 and/or KEAP1 is linked to poor response to conventional, targeted, and immune therapies.
“KRAS-mutant NSCLC with co-mutated STK11 and/or KEAP1 is particularly refractory to conventional, targeted, and immune therapy.”
- Also stated in: § INTRODUCTION · plain
“In NSCLC, for example, STK11 and/or KEAP1 mutations are associated with poor response to conventional, targeted, and immune therapies (5)(6)(7).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites (5)(6)(7)
Not checked in the free run.
- Also stated in: § INTRODUCTION · plain
- Study design and conductown data
Biological replicates in the CRISPR screens were strongly correlated, indicating high screen quality.
“Biological replicates were strongly correlated, indicating that the screens were high-quality (Supplementary.Fig. 1C).”
Quote in the paperSubstantial claim - Interpretationown data
The delayed kinetics of YAP nuclear translocation after MRTX-849 suggested a transcription-dependent process.
“The delayed kinetics of YAP nuclear translocation following MRTX-849 treatment suggested a transcription-dependent process.”
Quote in the paperNot a substantial claim - Premisecitation
Response rates to G12C inhibitors in KRAS G12C-mutant colorectal cancer are lower than in NSCLC.
“Response rates in KRAS G12C -mutant CRC are even lower (11).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Falchook, 2022, OA03.03 sotorasib in combination with RMC-4630, a SHP2 inhibitor, in KRAS p.G12C-mutated NSCLC and other solid tumors, J Thorac Oncol source
Not checked in the free run.
- Interpretationown data
Besides YAP/TAZ/TEAD, additional genes and pathways can be targeted to enhance G12C inhibitor efficacy.
“In concert, these data indicate that multiple other genes and pathways besides YAP/TAZ/TEAD could be targeted to enhance G12Ci efficacy.”
Quote in the paperSubstantial claim - Interpretationcitation
The Scribble mislocalization model may be more relevant to STK11-replete cells, since STK11-deficient cells should already have mislocalized Scribble.
“Although this model could be particularly relevant for STK11-replete cells, STK11-/cells should already have mislocalized Scribble (58).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [58] Adachi, 2023, Scribble mis-localization induces adaptive resistance to KRAS G12C inhibitors through feedback activation of MAPK signaling mediated by YAP-induced MRAS, Nat Cancer source
Not checked in the free run.
- Interpretationcitation
This level of YAP activation could contribute to the relative refractoriness of STK11-deficient NSCLC to multiple therapeutics.
“This level of YAP activation could contribute to the relative refractoriness of STK11-/-NSCLC to multiple therapeutics (58)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [58] Adachi, 2023, Scribble mis-localization induces adaptive resistance to KRAS G12C inhibitors through feedback activation of MAPK signaling mediated by YAP-induced MRAS, Nat Cancer source
Not checked in the free run.
- Interpretationown data
Combined G12C and TEAD inhibition shows increased efficacy over G12Ci alone in vivo and in vitro.
“Collectively, then, combined G12C and TEAD inhibition shows increased efficacy over G12Ci alone in vivo as well as in vitro.”
Quote in the paperSubstantial claim- Rests on an assumption: The KCL mouse model and H2030 xenografts model human KRAS G12C NSCLC response and resistance.
- Premisecitation
LKB1 activates the RHO-GEF DBL.
“Alternatively, or in addition, LKB1 activates DBL, a RHO-GEF(59).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [59] Mohseni, 2014, A genetic screen identifies an LKB1-MARK signalling axis controlling the Hippo-YAP pathway, Nat Cell Biol source
Not checked in the free run.
- Interpretationreasoning
The level of YAP activation seen in these cells is not sufficient to produce complete G12C inhibitor resistance in vitro or in vivo.
“but it is clearly inadequate to confer complete G12Ci resistance in vitro or in vivo.”
Quote in the paperSubstantial claim - Study design and conductown data
The YAP/TAZ/TEAD findings were validated genetically and pharmacologically across multiple cell lines, GEMM and CDX models, and two different modes of TEAD inhibition.
“We validated these findings genetically and pharmacologically using multiple cell lines, GEMM and CDX models, and two different modes of TEAD inhibition.”
Quote in the paperSubstantial claim - Premisecitation
Several feedback pathways act to limit YAP/TAZ/TEAD signaling.
“Multiple feedback pathways serve to limit YAP/TAZ/TEAD signaling (40)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [40] Franklin, 2023, Insights into recent findings and clinical application of YAP and TAZ in cancer, Nat Rev Cancer source
Not checked in the free run.
- Interpretationreasoning
The failure of earlier studies to detect most shared synthetic lethal genes is most likely explained by differences in screening conditions, cell systems including histotype and co-mutations, the number of lines surveyed, and the clinical development stage of the G12C inhibitors used.
“most likely because of differences in screening conditions, cell systems (including tumor histotype and co-mutations), the number of lines surveyed, and possibly the use of G12Cis at different stages of clinical development.”
Quote in the paperNot a substantial claim - Premisecitation
Suppressing ERK/MAPK signaling in cancer cells can increase RHOA activation.
“while suppressing ERK/MAPK signaling in cancer cells can result in increased RHOA activation (63).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [63] Qiu, 1995, A role for Rho in Ras transformation, Proc Natl Acad Sci USA source
Not checked in the free run.
- Interpretationown data
The synthetic lethality observed with DNA damage genes of the Fanconi anemia pathway suggests that G12C inhibitors could synergize with some conventional chemotherapy agents.
“the synthetic lethality with DNA damage genes (Fanconi anemia pathway, Fig. 1E) suggests the potential for synergy between G12Cis and some conventional chemotherapy agents.”
Quote in the paperSubstantial claim
- May combine two claims. 46
- Classified as probably not a substantial claim. 36
May combine two claims.
Findingown dataMore than 40 genes were depleted at FDR<0.1 in at least three of the four cell lines, and about 330 dropped out in at least two.
“More than 40 genes were depleted (FDR<0.1) in at least three lines (Fig. 1D); even more (~330) “dropped out” in at least two (Supplementary Table 2).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataOverexpression of TEAD1, WWTR1, YAP1, or constitutively active YAP S6A in KCL cells caused resistance to MRTX-849.
“Conversely, overexpression of TEAD1 (Fig. 2D; Supplementary Fig. 2D), WWTR1 (Fig. 2E; Supplementary Fig. 2E), YAP1 (Fig. 2F; Supplementary Fig. 2F), or a constitutively active, nucleus-restricted form of YAP1 (38), YAP S6A (Fig. 2G; left panel; Supplementary Fig. 2G) in “KCL” cells (derived from KRAS G12C ;Stk11-/-mice; see Methods) caused drug resistance.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [38] Rosenbluh, 2012, beta-Catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis, Cell source
Not checked in the free run.
May combine two claims.
Findingown dataNovel parallel targets among shared synthetic lethal pathways included DNA damage/Fanconi anemia, heparan sulphate metabolism, glycosylation, and translation initiation.
“Others included potential novel, parallel targets, including DNA damage (Fanconi anemia pathway), heparan sulphate metabolism, glycosylation, and translation initiation pathways”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataHippo (YAP/TAZ) pathway genes were enriched among dropouts from three of four lines; TEAD1 and WWTR1 were each synthetic lethal in two lines, and YAP1 showed significant dropout in H2030.
“Genes belonging to the Hippo (YAP/TAZ) pathway (colored blue) were enriched in dropouts from 3/4 lines; moreover, TEAD1 and WWTR1 (encoding TAZ) were each SL in two lines, while YAP1 showed significant dropout in H2030”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataExpected shared synthetic lethal pathways included MAPK family signaling, PI3K/AKT/mTOR, FGF, PDGF, autophagy, C-MYC, and E2F targets.
“including MAPK Family Signaling, PI3K/AKT/mTOR Signaling, FGF Signaling, PDGF Signaling, Autophagy, C-MYC Pathway and E2F targets.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataEnrichr analysis found synthetic lethal pathways shared in at least two lines, with most common to three or four.
“Enrichr analysis revealed SL pathways (p<0.05)shared in at least two lines, with most common to three or four (Fig. 1E).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataGenes encoding VRK1, RIOK2, PKN, elongator components ELP2/3/4/5, metabolic genes PGD/PGM3, and EXT1/EXT2 were among the depleted hits.
“including three serine/threonine kinases (VRK1, RIOK2, PKN), multiple components of the elongator complex (ELP2, ELP3, ELP4, ELP5), metabolic genes (PGD, PGM3), and genes (EXT1, EXT2) involved in heparan sulfate biosynthesis”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAt full doses, MRTX-849 was active against KCL syngeneic tumor grafts and H2030 xenografts, producing complete responses after 30 days.
“At full doses (100 mg/kg/d), MRTX-849 is quite active against KCL syngeneic tumor grafts and H2030 cell-derived xenografts, resulting in complete responses (no detectable tumor) after 30 days of treatment.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataELP5 was a significant synthetic lethal gene in the MRTX-849 plus TNO-155 screen, and ELP5 siRNA enhanced the effect of that drug combination.
“ELP5 also scored as a significant SL gene in the MRTX-849 + TNO-155 screen (Fig. 4A), and ELP5 siRNA enhanced the effect of this combination (Fig. 7F).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSeveral genes were synthetic lethal with single-agent MRTX-849 and with MRTX-849/TNO-155, while others were unique to one treatment.
“Several genes were SL with single agent MRTX-849 and with MTRX-849/TNO-155 (indicated in red); others were unique to one treatment”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAdding SHP099 to MRTX-849 after recurrence produced partial responses, but tumors resistant to both agents soon recurred.
“Addition of SHP099 resulted in partial responses, but tumors resistant to both agents (Combo-resistant tumors) soon recurred”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataTEAD and/or TAZ were induced in RPPAs of nodules from MRTX-849/SHP099-treated mice.
“Notably, TEAD and/or TAZ were also induced in RPPAs of nodules from MRTX-849/SHP099-treated mice”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataHippo and RHO GTPase signaling genes were enriched in both resistant patient tumors, along with glycolysis, MYC, glycosylation, and mTOR signaling genes.
“Importantly, Hippo and RHO GTPase signaling genes were enriched in both resistant tumors, along with glycolysis, MYC, glycosylation and mTOR signaling genes.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataShared synthetic lethal pathways in combination screens included PI3K/mTOR signaling, glycolysis, and N-linked glycosylation; pathways unique to combination-treated cells included Signaling by ALK and Central Carbon Metabolism.
“shared SL pathways (PI3K/mTOR signaling, Glycolysis, N-linked glycosylation) were identified, but those (Signaling by ALK, Central Carbon Metabolism) unique to combination-treated cells also emerged”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAfter drug withdrawal, tumors recurred, indicating some malignant cells remained.
“Some malignant cells remain, however, because after drug withdrawal, tumors recur.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataTEAD1 or TEAD4 were hits in the MRTX849/TNO155 screen, and Hippo signaling genes were enriched as synthetic lethal in the combination screen.
“Notably, TEAD1 or TEAD4 were hits in the MRTX849/TNO155 screen (Supplementary Fig. 4D), and genes annotated “Hippo signaling” were enriched as SL in the combination screen (Fig. 4B).”
Quote in the paperSubstantial claimMay combine two claims.
FindingcitationSome hits from earlier CRISPR screens overlap with shared dependencies found in this study, including ELP3, ELP4, PKN2 and RPN1 in H358, EXT1, WWTR1 and SHOC2 in MIAPaCa-2, and PGM3 in the 2D component of the 2D versus 3D screen.
“The “hits” in the earlier papers reveal some shared dependencies with our study (e.g., ELP3, ELP4, PKN2, RPN1 in the H358 screen; EXT1, WWTR1, SHOC2 in MIAPaCa-2 cells, PGM3 in the 2D component of the 2D vs 3D screen; compare with Fig. 1D with References 43,44).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
Findingown dataMYF-03-176 and VT-104 showed higher IC50s in YAP1-overexpressing KCL cells, arguing their effects were on-target.
“MYF-03-176 and VT-104 each showed higher IC50s (combined with MRTX-849 at its IC50 dose) in YAP1 over-expressing KCL cells, arguing that their effects were on-target”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataVRK1, ELP3 and ELP5 expression were significantly increased in the AMG-510-resistant patient sample, while RIOK2 levels were only nominally increased.
“VRK1, ELP3, and ELP5 expression were significantly increased in the AMG-510-resistant patient sample, while RIOK2 levels were nominally increased (Supplementary Table S10).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataInhibiting the RHO effector ROCK blocks MRTX-849-induced YAP nuclear translocation and adaptive resistance.
“inhibiting the RHO effector ROCK blocks MRTX-849-induced YAP nuclear translocation and adaptive resistance.”
- Also stated in: § STATEMENT OF SIGNIFICANCE · plain
“ROCK inhibitor treatment impairs MRTX-849-induced YAP1 nuclear localization.”
Quote in the paperSubstantial claim- Also stated in: § STATEMENT OF SIGNIFICANCE · plain
Classified as probably not a substantial claim.
Findingnone givenVRK2 is expressed in NSCLC.
“By contrast, VRK2 is expressed in NSCLC.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe study validated two kinases, VRK1 and RIOK2, and two tRNA-modifying enzymes, ELP3 and ELP5, that scored as G12C inhibitor synthetic lethal genes.
“we also validated two kinases (VRK1, RIOK2) and two tRNA-modifying enzymes (ELP3, ELP5) that scored as G12Ci SL genes.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationYAP/TAZ pathway activation is a known resistance mechanism to RAF V600E and MEK inhibitors.
“YAP/TAZ pathway activation is also a known mechanism of resistance to other targeted therapies, including RAF V600E and MEK inhibitors (36).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [36] Nguyen, 2019, YAP/TAZ signaling and resistance to cancer therapy, Trends Cancer source
Not checked in the free run.
May combine two claims.
InterpretationcitationMultiple intrinsic and acquired resistance mechanisms to G12C inhibitors are known, and drug combinations will likely be required to maximize their clinical efficacy in NSCLC and other diseases.
“Multiple mechanisms of intrinsic and acquired resistance (10,12,13), have been identified; hence, drug combinations will likely be needed to maximize the clinical efficacy of G12Cis (and probably other, emerging KRAS inhibitors) in NSCLC and other diseases.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [10] Janne, 2022, Adagrasib in non-small-cell lung cancer harboring a KRAS(G12C) mutation, N Engl J Med source
Not checked in the free run.
- cites [12] Skoulidis, 2021, Sotorasib for lung cancers with KRAS p.G12C mutation, N Engl J Med source
Not checked in the free run.
- cites [13] de Langen, 2023, Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRAS(G12C) mutation: a randomised, open-label, phase 3 trial, Lancet source
Not checked in the free run.
May combine two claims.
Interpretationown dataThe study's results credential TEAD inhibition as a strategy to enhance adagrasib and likely sotorasib response and identify other potentially druggable combination targets.
“Our results credential TEAD inhibition as a potential strategy for enhancing adagrasib (and likely sotorasib) response and identify multiple other potentially “druggable” targets for combination therapy.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCo-mutations of tumor suppressor genes such as TP53, SMARCA4, STK11, and/or KEAP1 commonly accompany KRAS mutations.
“Concomitant mutation or deletion (hereafter, “co-mutations”) of different tumor suppressor genes (e.g., TP53, SMARCA4, STK11, and/or KEAP1) typically occur in concert with KRAS mutations (4,5).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [4] Arbour, 2018, Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer, Clin Cancer Res source
Not checked in the free run.
- cites [5] Skoulidis, 2015, Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities, Cancer Discov source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationRHO/ROCK signaling can promote YAP activation, and Rhoa is required for mutant Kras-induced NSCLC in mice.
“RHO/ROCK signaling can promote YAP activation; also, Rhoa is required for mutant Kras-induced NSCLC in mice (42).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [42] Konstantinidou, 2013, RHOA-FAK is a required signaling axis for the maintenance of KRAS-driven lung adenocarcinomas, Cancer Discov source
Not checked in the free run.
May combine two claims.
PremisecitationG12C inhibitor plus SHP2 inhibitor combinations such as TNO155 and RMC-4550 have been validated preclinically and are being explored clinically.
“For example, combinations of G12Ci and SHP2 inhibitors (SHP2i) such TNO155 (14) and RMC-4550 (15) have been validated pre-clinically and are now being explored in the clinic (NCT04699188, NCT05480865).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [14] Weiss, 2022, Discovery, preclinical characterization, and early clinical activity of JDQ443, a structurally novel, potent, and selective covalent oral inhibitor of KRASG12C, Cancer Discov source
Not checked in the free run.
- cites [15] Ryan, 2022, KRAS(G12C)-independent feedback activation of wild-type RAS constrains KRAS(G12C) inhibitor efficacy, Cell Rep source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationKRAS driver mutations occur in about 25-30% of NSCLC cases, and roughly half of these are G12C.
“Mutations in KRAS drive 25-30% of NSCLC cases (1)(2)(3); approximately half of these mutations convert glycine 12 to cysteine (G12C).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites (1)(2)(3)
Not checked in the free run.
May combine two claims.
PremisecitationIn NSCLC, G12C inhibitors produce overall response rates of 30-40%, disease control around 60%, and median duration under one year.
“While these drugs clearly have clinical activity, overall response rates (30-40%) and disease control (~60%) in NSCLC are modest and transient, with median duration less than one year (9,10).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [9] Dy, 2023, Long-term outcomes and molecular correlates of sotorasib efficacy in patients with pretreated KRAS G12C-mutated non-small-cell lung cancer: 2-year analysis of CodeBreaK 100, J Clin Oncol source
Not checked in the free run.
- cites [10] Janne, 2022, Adagrasib in non-small-cell lung cancer harboring a KRAS(G12C) mutation, N Engl J Med source
Not checked in the free run.
May combine two claims.
Interpretationown dataThe findings indicate that nuclear YAP1 and/or TAZ binding TEAD1 or other TEAD family members can antagonize G12Ci action and cause resistance.
“Collectively, these findings indicate that YAP1 and/or TAZ, acting in the nucleus by binding TEAD1 (or other TEAD family members), can antagonize G12Ci action and cause resistance.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTEAD inhibitors are in clinical trials for NF2-mutant mesothelioma and other indications.
“TEAD inhibitors are in clinical trials for NF2-mutant mesothelioma and other indications (e.g., NCT05228015 and NCT04665206) (35).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [35] Pobbati, 2023, Therapeutic targeting of TEAD transcription factors in cancer, Trends Biochem Sci source
Not checked in the free run.
May combine two claims.
InterpretationcitationRHO levels are probably lower in STK11-deficient than in STK11-replete cells, and therefore too low to drive enough YAP translocation and activation to cause resistance.
“Hence, RHO levels are likely to be lower in STK11-/-, compared with STK11-replete cells, and thus inadequate to drive sufficient YAP translocation/activation to confer resistance.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationSHP2 inhibition enhances G12Ci action in vitro and in mice.
“We and others reported previously that SHP2 inhibition enhances G12Ci action in vitro and in mice (16,45,46)”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [16] Fedele, 2021, SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling, J Exp Med source
Not checked in the free run.
- cites [45] Ryan, 2020, Vertical pathway inhibition overcomes adaptive feedback resistance to KRAS(G12C) inhibition, Clin Cancer Res source
Not checked in the free run.
- cites [46] Ahmed, 2019, SHP2 drives adaptive resistance to ERK signaling inhibition in molecularly defined subsets of ERK-dependent tumors, Cell Rep source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationLKB1, encoded by STK11, antagonizes YAP activation by activating a PAR1-Scribble-MST2-LATS pathway.
“previous work showed that LKB1 (encoded by STK11) antagonizes YAP activation by activating a PAR1->Scribble->MST2->LATs pathway”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [58] Adachi, 2023, Scribble mis-localization induces adaptive resistance to KRAS G12C inhibitors through feedback activation of MAPK signaling mediated by YAP-induced MRAS, Nat Cancer source
Not checked in the free run.
May combine two claims.
Interpretationown dataThe findings suggested that MRTX-849 treatment evokes a transcriptional program leading to increased integrin activation, cytoskeletal reorganization, actomyosin contractility, RHO activation, and YAP/TAZ pathway activation.
“Collectively, these findings suggested that MRTX-849 treatment evokes a transcriptional program leading to increased integrin activation, cytoskeletal reorganization, actomyosin contractility, RHO activation and, consequently YAP/TAZ pathway activation.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataMice were randomized to treatment groups when tumor volumes reached about 100 mm3 for syngeneic grafts or about 300 mm3 for xenografts.
“When tumor volumes reached ~100 mm 3 (for syngeneic grafts) or ~300 mm 3 (for xenografts), mice were randomized to the following groups: vehicle control, MRTX-849 (100 mg/kg/d), VT104 (10 mg/kg/d), and MRTX-849 (100mg/kg/d) and VT104 (10 mg/kg/d).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationAdachi and colleagues reported that G12C inhibitor treatment causes Scribble mislocalization, which reduces MST2/LATS suppression of YAP nuclear localization.
“They reported that G12Ci treatment induces Scribble mislocalization, which leads to decreased MST2/LATS suppression of YAP nuclear localizaton.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningThese feedback pathways dampen YAP activation in STK11-deficient cells, which helps explain why such cells are not fully resistant to G12C inhibitors.
“which dampen YAP activation in STK11-deficient cells and help explain this apparent paradox.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationEarlier work links the YAP/TAZ/TEAD pathway to resistance to other targeted therapies, including MEK and BRAF V600E inhibitors.
“These findings comport with previous results implicating the YAP/TAZ/TEAD pathway in resistance to other targeted therapies (40,41) including MEKi and BRAF V600E inhibitors (36,55).”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [40] Franklin, 2023, Insights into recent findings and clinical application of YAP and TAZ in cancer, Nat Rev Cancer source
Not checked in the free run.
- cites [41] Piccolo, 2023, YAP/TAZ as master regulators in cancer: modulation, function and therapeutic approaches, Nat Cancer
Not checked in the free run.
- cites [36] Nguyen, 2019, YAP/TAZ signaling and resistance to cancer therapy, Trends Cancer source
Not checked in the free run.
- cites [55] Han, 2020, CRISPR screens in cancer spheroids identify 3D growth-specific vulnerabilities, Nature source
Not checked in the free run.
May combine two claims.
Premiseown dataVT-104 is a clinical grade, non-covalent, pan-TEAD inhibitor that binds the TEAD palmitate pocket.
“VT-104 is a clinical grade, non-covalent, pan-TEAD inhibitor that also binds this pocket.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationMYF-03-69 is a tool compound that covalently binds the conserved TEAD palmitate pocket, irreversibly disrupting YAP-TEAD association and suppressing TEAD1-4 transcriptional activity.
“MYF-03-69 is a tool compound that binds covalently to the conserved TEAD palmitate pocket, irreversibly disrupting YAP-TEAD association and suppressing TEAD1-4 transcriptional activity (48).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [48] Fan, 2022, Covalent disruptor of YAP-TEAD association suppresses defective Hippo signaling, eLife source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationPreliminary results indicate that the TEAD inhibitor VT3989 is safe with manageable toxicity.
“preliminary results indicate that at least one, VT3989, is safe with manageable toxicity (19).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [19] Olivieri, 2021, Genome-scale chemogenomic CRISPR screens in human cells using the TKOv3 library, STAR Protoc source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationOther TEAD inhibitors are already being tested in phase 1 clinical trials.
“Other TEAD inhibitors are already in phase 1 clinical trials (NCT05228015 and NCT04665206)”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites NCT05228015
Not checked in the free run.
- cites NCT04665206
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationHagenbeek and colleagues developed allosteric TEAD inhibitors and showed that they block adaptive resistance to G12C inhibitor treatment.
“Hagenbeek et al. (56) reported the development of allosteric TEAD inhibitors and demonstrated their ability to block adaptive resistance to G12Ci treatment”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [56] Dey, 2020, Targeting the Hippo pathway in cancer, fibrosis, wound healing and regenerative medicine, Nat Rev Drug Discov source
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.
InterpretationreasoningThe need for combination therapy is especially pressing for NSCLC with STK11 and/or KEAP1 co-mutations and for other KRAS G12C tumor types such as colorectal cancer.
“This need is particularly acute for the NSCLC subgroups with co-mutations in STK11 and/or KEAP1, as well as for tumors of other histotypes (e.g., CRC) with KRAS G12C mutations.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAdachi and colleagues observed G12C inhibitor-induced YAP translocation in STK11-replete H358 cells and in the STK11-deficient LU65 line.
“Adachi et al. also observed G12Ci-induced YAP translocation in STK11-replete H358 cells and in LU65 cells, which are STK11-/-”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAdachi and colleagues found effects of YAP1 deficiency similar to TEAD inhibition in a small number of NSCLC lines and H358 xenografts.
“Adachi et al. (57) found similar effects of YAP1 deficiency in a limited number of NSCLC lines and H358 xenografts.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [57] Hagenbeek, 2023, An allosteric pan-TEAD inhibitor blocks oncogenic YAP/TAZ signaling and overcomes KRAS G12C inhibitor resistance, Nat Cancer source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenCell lines were tested for mycoplasma contamination by PCR 5-7 days after thawing.
“Lines were tested for mycoplasma contamination by PCR 5-7 days after thawing.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMultiple SHP2 inhibitors are in clinical trials for KRAS G12C-mutant tumors and other indications.
“multiple SHP2i are in clinical trials for KRAS G12C -mutant tumors and other indications (e.g., NCT05480865, NCT03565003, NCT04916236, NCT04699188) (47).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [47] Kerr, 2021, Allosteric SHP2 inhibitors in cancer: Targeting the intersection of RAS, resistance, and the immune microenvironment, Curr Opin Chem Biol source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenAnimal studies were approved by the Institutional Animal Care and Use Committee at New York University Grossman School of Medicine and adhered to the Guide for the Care and Use of Laboratory Animals.
“All animal studies were approved by the Institutional Animal Care and Use Committee at New York University Grossman School of Medicine and adhered to the guidelines stipulated in the Guide for the Care and Use of Laboratory Animals.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
InterpretationreasoningThe study's results offer a landscape of candidate targets for future combination strategies, some of which can be tested quickly in the clinic and others of which need new drug development.
“Our results provide a landscape of potential new targets for future combination strategies, some of which can be tested rapidly in the clinic, others of which will require new drug development.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductnone givenStatistical significance was set at P=0.05 for all analyses except screen data, where genes with FDR<0.1 were considered for further analysis.
“Significance was set at P = 0.05 for all analyses except screen data, where genes with FDR<0.1 were considered for further analysis.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenYAP localization in cell populations was quantified by two double-blinded observers.
“YAP localization in cell populations was quantified by two double-blinded observers.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataHuman lung tumor specimens were collected with written informed consent and IRB approval.
“Human lung tumor specimens were collected from patients at New York University Langone Hospital (New York, NY) with patient written informed consents and the approval from the Institute Research Ethics Committee and with the approval of the Institutional Review Board, in accordance with the Declaration of Helsinki, CIOMS, Belmont Report, and U.S. Common Rule.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningBecause several resistance mechanisms to G12C inhibitors exist, combination therapies will be needed to maximize the benefit of these drugs.
“The existence of multiple G12Ci resistance mechanisms indicates that combination therapies will be required to maximize the impact of these remarkable drugs.”
Quote in the paperNot a substantial claim- Rests on an assumption: KRAS G12C inhibitors have so far produced only modest efficacy in the clinic.
May combine two claims.
Interpretationown dataThese results suggest TEAD inhibition could augment the MRTX-849/TNO155 combination as well as single-agent MRTX-849.
“These results suggest that TEAD inhibition could augment this drug combination as well as single agent MRTX-849.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationVRK1 was previously described as a collateral lethality in glioblastoma because its paralog VRK2 is methylated and not expressed in that cancer.
“VRK1 was previously reported as a “collateral lethality” in glioblastoma, owing to methylation and lack of expression of its paralog VRK2 in this malignancy.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationRHO promotes YAP activation through the actomyosin cytoskeleton.
“RHO, acting though the actomyosin cytoskeleton, is also known to promote YAP activation (40,41).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [40] Franklin, 2023, Insights into recent findings and clinical application of YAP and TAZ in cancer, Nat Rev Cancer source
Not checked in the free run.
- cites [41] Piccolo, 2023, YAP/TAZ as master regulators in cancer: modulation, function and therapeutic approaches, Nat Cancer
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationRHOA is required for Kras G12D-driven lung adenocarcinoma.
“and for Kras G12D -driven lung adenocarcinoma (42)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [42] Konstantinidou, 2013, RHOA-FAK is a required signaling axis for the maintenance of KRAS-driven lung adenocarcinomas, Cancer Discov source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationRHOA is required for transformation induced by mutant KRAS.
“earlier work found that RHOA is necessary for the transformation induced by mutant KRAS (60)(61)(62)”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [60] Xu, 2010, LKB1 tumor suppressor protein regulates actin filament assembly through Rho and its exchange factor Dbl independently of kinase activity, BMC Cell Biol source
Not checked in the free run.
- cites [61] Khosravi-Far, 1995, Activation of Rac1, RhoA, and mitogen-activated protein kinases is required for Ras transformation, Mol Cell Biol source
Not checked in the free run.
- cites [62] Chen, 2003, Oncogenic Ras leads to Rho activation by activating the mitogen-activated protein kinase pathway and decreasing Rho-GTPase-activating protein activity, J Biol Chem source
Not checked in the free run.
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PremisecitationAdachi and colleagues reported that activated YAP increases MRAS expression, which bypasses adaptive resistance to G12C inhibitors by promoting assembly of the MRAS/SHOC2/PP1 complex.
“Adachi et al. also reported that, once activated, YAP drives increased expression of MRAS, which, by promoting assembly of the MRAS/SHOC2/PP1 complex, bypasses adaptive resistance to G12Ci.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSTK11 is a critical regulator of metabolism through its substrate AMPK.
“STK11 is also a critical regulator of metabolism via its substrate AMPK (73).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [73] Mukhopadhyay, 2021, The metabolic landscape of RAS-driven cancers from biology to therapy, Nat Cancer source
Not checked in the free run.
May combine two claims.
PremisecitationDepleting VRK1 in VRK2-deficient cells causes G2/M arrest followed by DNA damage.
“VRK1 depletion in these VRK2-deficient cells levels leads to a G2/M phase arrest, followed by DNA damage (67,68).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMutant KRAS is a well-known regulator of glycolysis.
“Mutant KRAS is a well known regulator of glycolysis (72)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [72] Cruz-Gordillo, 2020, ELP-dependent expression of MCL1 promotes resistance to EGFR inhibition in triple-negative breast cancer cells, Sci Signal source
Not checked in the free run.
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PremisecitationSuppression of ELP1 or ELP3 can abrogate vemurafenib activity in BRAF V600E melanoma.
“Previous research showed that suppression of ELP1 or ELP3 can abrogate vemurafenib in BRAF V600E melanoma (70)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [70] Cerezo, 2021, RIOK2 phosphorylation by RSK promotes synthesis of the human small ribosomal subunit, PLoS Genet source
Not checked in the free run.
May combine two claims.
PremisecitationROCK inhibitors are not associated with proteinuria and could therefore avoid the main side effect of TEAD inhibition.
“ROCK inhibitors are not associated with proteinuria, and thus could avoid the major drug-related side effect of TEAD inhibition (65).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [65] Zhao, 2006, Effect of fasudil hydrochloride, a protein kinase inhibitor, on cerebral vasospasm and delayed cerebral ischemic symptoms after aneurysmal subarachnoid hemorrhage, Neurol Med Chir (Tokyo) source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationRIOK2 is a relatively unexplored RSK target whose normal function is to promote maturation of the 40S ribosome.
“RIOK2 is a relatively unexplored RSK target whose normal function is to promote maturation of the 40S ribosome (69).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [69] So, 2022, VRK1 as a synthetic lethal target in VRK2 promoter-methylated cancers of the nervous system, JCI Insight source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationELP proteins contribute to EGFR inhibitor resistance in breast cancer cells by promoting MCL1 synthesis.
“and that ELPs contribute to EGFR inhibitor resistance in breast cancer cells by promoting MCL1 synthesis (71).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [71] Rapino, 2018, Codon-specific translation reprogramming promotes resistance to targeted therapy, Nature source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPrevious studies have revealed a complex, bidirectional interplay between the Hippo pathway and glucose metabolism.
“previous studies have revealed complex, bidirectional interplay between the Hippo pathway and glucose metabolism (74).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [74] Shackelford, 2009, The LKB1-AMPK pathway: metabolism and growth control in tumour suppression, Nat Rev Cancer source
Not checked in the free run.
Probably not a substantial claim: may not pass S4 (based).
InterpretationreasoningVRK1 must have specific functions in G12C inhibitor-treated NSCLC cells.
“VRK1 must have specific functions in G12Ci-treated NSCLC cells.”
Quote in the paperNot a substantial claim- The authors state this as an assumption: VRK2 is expressed at the protein level in NSCLC.
The paper relies on this without support.
The four KRAS G12C-mutant NSCLC cell lines with STK11 and KEAP1 co-mutations are representative of KRAS G12C-mutant NSCLC with these co-mutations.
“we chose lines with co-mutations in STK11; three were also KEAP1-defective.”
The paper relies on this without support.
CRISPR/Cas9 dropout under drug treatment in these cell lines identifies genes whose inactivation enhances drug efficacy.
“we used genomewide CRISPR/Cas9 screening to identify genes whose inactivation enhances the efficacy of MRTX-849 alone or in combination with TNO-155 in four KRAS G12C -mutant NSCLC cell lines.”
The paper relies on this without support.
The KCL mouse model and H2030 xenografts model human KRAS G12C NSCLC response and resistance.
“we developed G12Ci-and G12Ci+SHP2i-resistant genetically engineered mouse models (GEMMs, see Methods for details).”
The paper relies on this without support.
Enriched pathways in resistant mouse and patient tumors indicate resistance mechanisms relevant to human KRAS G12C NSCLC.
“resistance pathways suggested by our CRISPR/ Cas9 SL screens and the resistant GEMMs also were enriched in these patient samples.”
The paper relies on this without support.
KRAS G12C inhibitors have so far produced only modest efficacy in the clinic.
“yet their efficacy in the clinic has thus far been modest.”
The authors state this as an assumption.
VRK2 is expressed at the protein level in NSCLC.
“assuming that VRK2 is also expressed at the protein level”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
One major regulator for resistance against KRASG12C inhibitors is driven by the Hippo (YAP/TAZ) signaling pathway with nuclear translocation of YAP.
“One of the major regulators for resistance against KRASG12C inhibitors is driven by the Hippo (YAP/TAZ) signaling pathway with nuclear translocation of YAP, providing some potential targets to overcome resistance [28].”
From KRAS, a New Target for Precision Medicine in Colorectal Cancer? (2024) · cites this paper as [28]
KRAS mutations drive the upregulation of key enzymes, such as PCK1, PCK2, and ASS1, which are involved in aspartate and urea cycle metabolism, contributing to the metabolic flexibility of KRAS-mutant CRC cells.
“KRAS mutations drive the upregulation of key enzymes, such as PCK1, PCK2, and ASS1, which are involved in aspartate and urea cycle metabolism, contributing to the metabolic flexibility of KRAS-mutant CRC cells [33,34,35].”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [34]
Oncogenic KRAS significantly reprograms cellular metabolism, enhancing glycolysis, glutaminolysis, and aspartate metabolism to fuel tumor growth and survival.
“Oncogenic KRAS significantly reprograms cellular metabolism, enhancing glycolysis, glutaminolysis, and aspartate metabolism to fuel tumor growth and survival.”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [34]
PI3K inhibitors have shown promise in preclinical models to overcome these resistance mechanisms.
“PI3K inhibitors have shown promise in preclinical models to overcome these resistance mechanisms [34]”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [34]
PI3K pathway alterations, such as PTEN loss, enable tumors to bypass KRAS G12C/SHP2 inhibition and sustain growth.
“PI3K pathway alterations, such as PTEN loss, enable tumors to bypass KRAS G12C/SHP2 inhibition and sustain growth.”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [34]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
TEAD inhibitor identity differs between the results and Figure 5
MinorThe results identify MYF-03-69 as the tool compound tested with MRTX-849, but the Figure 5 legend names MYF-03-176 for that combination assay. The text does not establish that these are the same compound.
“We next tested the effects of two mechanistically distinct TEAD inhibitors on MRTX-849 efficacy.MYF-03-69 is a tool compound that binds covalently to the conserved TEAD palmitate pocket”
“H2122, H2030, HCC-44, and H23 lines treated with MYF-03-176 (1μM) and MRTX-849 (at IC50 for each line) alone or in combination.”
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Klomp, J. E., Diehl, J. N., Klomp, J. A., Edwards, A. C., Yang, R., Morales, A. J., Taylor, K. E., Drizyte-Miller, K., Bryant, K. L., Schaefer, A., et al. (2024) · Science · doi:10.1126/science.adk0850 · Cited by 83 · see citing works
TEAD Inhibition Overcomes YAP1/TAZ-Driven Primary and Acquired Resistance to KRASG12C Inhibitors
Edwards, A. C., Stalnecker, C. A., Jean Morales, A., Taylor, K. E., Klomp, J. E., Klomp, J. A., Waters, A. M., Sudhakar, N., Hallin, J., Tang, T. T., et al. (2023) · Cancer Research · doi:10.1158/0008-5472.can-23-2994 · Cited by 91 · see citing works
Self-citationYAP/TEAD inhibitor VT3989 in solid tumors: a phase 1/2 trial
Yap, T. A., Kwiatkowski, D. J., Dagogo‐Jack, I., Offin, M. D., Zauderer, M. G., Kratzke, R. A., Desai, J., Body, A. L., Millward, M., Tolcher, A. W., et al. (2025) · Nature Medicine · doi:10.1038/s41591-025-04029-3 · Cited by 81 · see citing works
Self-citationTakeda, M., Yoshida, S., Inoue, T., Sekido, Y., Hata, T., Hamabe, A., Ogino, T., Miyoshi, N., Uemura, M., Yamamoto, H., et al. (2025) · Cancers · doi:10.3390/cancers17030428 · Cited by 82 · see citing works
“PI3K inhibitors have shown promise in preclinical models to overcome these resistance mechanisms [34].”
Targeting the Hippo pathway in cancer
Harvey, K. F., & Tang, T. T.-L. (2025) · Nature Reviews Drug Discovery · doi:10.1038/s41573-025-01234-0 · Cited by 65 · see citing works
“Subsequently, unbiased genetic studies revealed YAP as a gene that can supplant the oncogenic activity of KRAS 136,137 , and that YAP hyperactivation can drive resistance to RAS–MAPK pathway-targeted therapies, such as inhibitors specific for BRAF, MEK and KRAS 138–140 .”
Self-citationKumarasamy, V. M., Frangou, C. G., Wang, J., Wan, Y., Dynka, A., Rosenheck, H. R., Dey, P., Abel, E. V., Knudsen, E. S., & Witkiewicz, A. K. (2024) · Cancer Research · doi:10.1158/0008-5472.can-23-2504 · Cited by 56 · see citing works
Hippo Signaling at the Hallmarks of Cancer and Drug Resistance
Kumar, R., & Hong, W. (2024) · Cells · doi:10.3390/cells13070564 · Cited by 47 · see citing works
“In a genome-wide CRISPR/Cas9 screening, TEAD inhibition was identified to be synthetically lethal to KRAS G12Ci, credentialing the ability of TEAD inhibition to enhance KRAS G12Ci efficacy [57].”
BackgroundThe Hippo pathway: Organ size control and beyond
Guo, P., Wan, S., & Guan, K. (2024) · Pharmacological Reviews · doi:10.1016/j.pharmr.2024.100031 · Cited by 45 · see citing works
MARK2/MARK3 Kinases Are Catalytic Codependencies of YAP/TAZ in Human Cancer
Klingbeil, O., Skopelitis, D. S., Tonelli, C., Yoshimoto, T., Alpsoy, A., Panepinto, M. C., Minicozzi, F., Merrill, J. R., Cafiero, A. M., Aggarwal, D., et al. (2024) · Cancer Discovery · doi:10.1158/2159-8290.cd-23-1529 · Cited by 31 · see citing works
A first-in-class EGFR-directed KRAS G12V selective inhibitor
Stanland, L. J., Huggins, H. P., Sahoo, S. S., Porrello, A., Chareddy, Y. S., Azam, S. H., Perry, J. L., Pallan, P. S., Whately, K. M., Edatt, L., et al. (2025) · Cancer Cell · doi:10.1016/j.ccell.2025.05.016 · Cited by 31 · see citing works
Emerging Targeted Therapies in Non-Small-Cell Lung Cancer (NSCLC)
Mina, S. A., Shanshal, M., Leventakos, K., & Parikh, K. (2025) · Cancers · doi:10.3390/cancers17030353 · Cited by 26 · see citing works
“Moreover, potentially targetable synthetic lethal genes, including serine–threonine kinases, tRNA-modifying and proteoglycan synthesis enzymes, and YAP/TAZ/TEAD pathway components, have also been identified as mechanisms of resistance [29,30].”
The ANGPTL4-HIF-1α loop: a critical regulator of renal interstitial fibrosis
Li, Y., Chen, S., Yang, Q., Liu, X., Zhou, W., Kang, T., Wu, W., & Ou, S. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05466-3 · Cited by 21 · see citing works
“For instance, recent studies have revealed that increased ANGPTL4 expression is closely associated with the invasiveness and drug resistance of KRAS G12D pancreatic cancer [5, 6], and researchers have explored the mechanisms of drug resistance in KRAS-mutant cancers [7].”
BackgroundŠereš, M., Spacayova, K., Sulová, Z., Špaldová, J., Breier, A., & Pavlíková, L. (2025) · Cancers · doi:10.3390/cancers17020248 · Cited by 26 · see citing works
Exploring Predictive and Prognostic Biomarkers in Colorectal Cancer: A Comprehensive Review
Ashouri, K., Wong, A., Mittal, P., Torres‐Gonzalez, L., Lo, J. H., Soni, S., Algaze, S. D., Khoukaz, T., Zhang, W., Yang, Y., et al. (2024) · Cancers · doi:10.3390/cancers16162796 · Cited by 19 · see citing works
“Mechanistic studies in lung cancer indicate that the hippo pathway is implicated in KRAS G12C resistance, highlighting its therapeutic potential in augmenting KRAS inhibitors [26].”
BackgroundLiao, P. (2025) · Toxicon · doi:10.1016/j.toxicon.2025.108553 · Cited by 18 · see citing works
Ibanez, K. R., Huang, T., & Lee, J.-M. (2024) · Cells · doi:10.3390/cells13121064 · Cited by 19 · see citing works
“Recently, targeting multiple modes of PI3K and its compensatory pathways like KRAS and YAP/YEAD has been suggested to benefit KRAS-driven tumors [98], but further investigation is needed in gynecological cancers.”
BackgroundTargeting the KRAS Oncogene for Patients with Metastatic Colorectal Cancer
Miao, R., Yu, J. B., & Kim, R. D. (2025) · Cancers · doi:10.3390/cancers17091512 · Cited by 18 · see citing works
Cellular and Molecular Mechanisms of Oxidative DNA Damage and Repair
Ayna, A., Çağlayan, C., & Tayşi, S. (2025) · Medicina · doi:10.3390/medicina61112013 · Cited by 21 · see citing works
“The CRISPR/Cas9 system enables the induction of precise DSBs or single-base damage at targeted genomic locations, thereby allowing direct visualization of repair protein recruitment and kinetics to damage sites [192,193].”
Advances in Targeted Therapy for Non-Small-Cell Lung Cancer: Current Progress and Future Directions
Peshin, S., Takrori, E., Yazji, J. H., Haque, J., Dharia, A. A., Mithani, M. S., Anum, F., Asfeen, U. Z., Couch, J. K., Donovan, M., et al. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262311517 · Cited by 14 · see citing works
“Studies have also identified synthetic lethal vulnerabilities involving kinases, tRNA-modifying enzymes, and the YAP/TAZ/TEAD axis [135,136].”
Overcoming Irinotecan Resistance by Targeting Its Downstream Signaling Pathways in Colon Cancer
Saurav, S., Karfa, S., Vu, T., Liu, Z., Datta, A., Manne, U., Samuel, T., & Datta, P. K. (2024) · Cancers · doi:10.3390/cancers16203491 · Cited by 13 · see citing works
“Targeting Hippo signaling in combination with the KRAS inhibitor showed an increased efficacy of the inhibitor on “undrug-gable” KRAS-inhibitor-resistant CRC, suggesting the involvement of Hippo signaling in chemoresistance [59].”
BackgroundscDrugMap: benchmarking large foundation models for drug response prediction
Wang, Q., Pan, Y., Zhou, M., Tang, Z., Wang, Y., Wang, G., & Song, Q. (2025) · Nature Communications · doi:10.1038/s41467-025-67481-2 · Cited by 12 · see citing works
KRAS, a New Target for Precision Medicine in Colorectal Cancer?
Boilève, A., Smolenschi, C., Lambert, A., Boige, V., Delaye, M., Camilleri, G. M., Tarabay, A., Valéry, M., Fuerea, A., Pudlarz, T., et al. (2024) · Cancers · doi:10.3390/cancers16203455 · Cited by 11 · see citing works
“The pan-RAS strategy adopted by Boehringer Ingelheim ® focuses on inhibitors of the switch I/II pocket, such as the compound BI-2865 [51,52].”
MethodInfluentialYang, F., Duan, Y., Li, Y., Zhu, D., Wang, Z., Luo, Z., Zhang, Y., Zhang, G., He, X., & Kang, X. (2024) · Molecular Medicine · doi:10.1186/s10020-024-00853-4 · Cited by 11 · see citing works
Precision immune regulation in KRAS-mutated cancers: the final piece of the puzzle?
Fu, S., Ma, J., Cai, C., Tan, J., Deng, X., Shen, H., Zeng, S., Chen, Y., & Han, Y. (2025) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-025-03444-1 · Cited by 11 · see citing works
Liu, M. R., Wu, S., Wu, H., Zhou, Y., Zhang, X., Zhu, D., & Jiang, J. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05277-6 · Cited by 9 · see citing works
“By elucidating the potential interactions between Ferredoxin 1 and KRAS G12C signaling pathways, it can identify additional targets for combination therapies or alternative treatment approaches to overcome resistance and improve the efficacy of existing KRAS G12C inhibitors [34, 35].”
BackgroundMaietta, I., Viscusi, E., Laudati, S., Iannaci, G., D’Antonio, A., Melillo, R. M., Motti, M. L., & Falco, V. D. (2024) · Cells · doi:10.3390/cells13181546 · Cited by 8 · see citing works
PKN2 Is a Dependency of the Mesenchymal-like Cancer Cell State
Killarney, S. T., Mesa, G., Washart, R., Mayro, B., Dillon, K. A., Wardell, S. E., Newlin, M., Lu, M., Rmaileh, A. A., Liu, N., et al. (2024) · Cancer Discovery · doi:10.1158/2159-8290.cd-24-0928 · Cited by 8 · see citing works
Advancements in Gene Therapy for Non-Small Cell Lung Cancer: Current Approaches and Future Prospects
Ziółkowska‐Suchanek, I., & Rozwadowska, N. (2025) · Genes · doi:10.3390/genes16050569 · Cited by 10 · see citing works
“In another study, S. Mukhopadhyay used genome-wide CRISPR/Cas9 screening to identify genes whose inactivation enhances the efficacy of two drugs (MRTX-849: adagrasib, KRAS G12C Inhibitor; TNO-155: SHP2i, inhibitor of wild-type SHP2 ) in four NSCLC cell lines with KRAS/STK11 -mutant NSCLC lines [53].”
Wang, S., Diao, S., Kim, H., Zou, J. Y., Li, K., & Koromilas, A. E. (2025) · Communications Biology · doi:10.1038/s42003-025-08740-2 · Cited by 8 · see citing works
Discovery of a Potent and Selective TEAD Degrader with Durable Degradation Activity
Cao, L., Yang, J., Liu, Y., Chen, X., Shi, Y., Zhao, Y., Zhang, Y., Chen, J., Li, B., Wen, W., et al. (2025) · Advanced Science · doi:10.1002/advs.202503277 · Cited by 8 · see citing works
Self-citationKRAS-targeted therapies in cancer: novel approaches and overcoming resistance
Tang, D., Kroemer, G., & Kang, R. (2025) · BMJ Oncology · doi:10.1136/bmjonc-2025-000946 · Cited by 10 · see citing works
Balakrishnan, K., Chen, Y., & Dong, J. (2024) · Cancers · doi:10.3390/cancers16091781 · Cited by 8 · see citing works
“Some studies reported that YAP1/TAZ activation causes drug resistance by downregulating various multidrug transporters [14,15].”
BackgroundNavigating Glioma Complexity: The Role of Abnormal Signaling Pathways in Shaping Future Therapies
Chen, Q., Jin, J., Li, P., Wang, X., & Wang, Q. (2025) · Biomedicines · doi:10.3390/biomedicines13030759 · Cited by 7 · see citing works
“When SHP2 inhibitors are used in combination with KRAS G12C inhibitors, the therapeutic effect may be enhanced by regulating this pathway [25].”
CRISPR-Cas9 Screening Identifies Resistance Mechanisms to KRAS Inhibition in Pancreatic Cancer
Lim, S.-A., Todd, H., Goodhart, G., Chang, W.-H., Amparo, A. M., Bridgens, R., Dilly, J., Park, S. J., Beal, R. M., Shehadeh, S. M., et al. (2025) · Cancer Research · doi:10.1158/0008-5472.can-25-1835 · Cited by 8 · see citing works
“We and others have recently determined that IAG933, a YAP/ TAZ-TEAD complex inhibitor, synergizes with KRAS G12C inhibitors to reduce growth in KRAS G12C -mutant PDAC by multiple mechanisms (27, 51).”
Diaz, F. C., Waldrup, B., Carranza, F., Manjarrez, S., & Velazquez-Villarreal, E. I. (2026) · Cancers · doi:10.3390/cancers18020293 · Cited by 6 · see citing works
Lactylation and acetylation: parallel paths, divergent deeds, and research dilemmas
Jiang, W., Chen, Y., Lin, S., Liu, Y., & Liao, X. (2026) · Journal of Translational Medicine · doi:10.1186/s12967-026-07877-w · Cited by 7 · see citing works
“The figure was drawn using Figdraw metabolic enzymes or modification regulators [34].”
Self-citationp53 Genetics and Biology in Lung Carcinomas: Insights, Implications and Clinical Applications
Benitez, D. A., Cumplido-Laso, G., Olivera-Gómez, M., Pino, N. D. V.-D., Díaz-Pizarro, A., Mulero‐Navarro, S., Román-García, A., & Carvajal-González, J. M. (2024) · Biomedicines · doi:10.3390/biomedicines12071453 · Cited by 7 · see citing works
“For example, small molecules that can reactivate mutant p53 proteins or induce synthetic lethality are under investigation [220–225].”
Voutsadakis, I. A. (2024) · Journal of Clinical Medicine · doi:10.3390/jcm13247635 · Cited by 7 · see citing works
“The effector transcription factors of the Hippo pathway, YAP/TAZ and TEAD, have been proposed as synthetic lethal with inhibition of the KRAS pathway in cells with aberrant activation due to KRAS G12C mutations [71].”
Song, C., & Zhao, C. (2024) · Journal of Microbiology and Biotechnology · doi:10.4014/jmb.2408.08026 · Cited by 6 · see citing works
“4) [129].”
Decoding driver and phenotypic genes in cancer: Unveiling the essence behind the phenomenon
Liu, D., Liu, L., Zhang, X., Zhao, X., Li, X., Che, X., & Wu, G. (2025) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2025.101358 · Cited by 6 · see citing works
YAP/TAZ Promote GLUT1 Expression and Are Associated with Prognosis in Endometrial Cancer
Fujita, M., Orisaka, M., Mizutani, T., Fujita, Y., Onuma, T., Tsuyoshi, H., & Yoshida, Y. (2025) · Cancers · doi:10.3390/cancers17152554 · Cited by 6 · see citing works
“Furthermore, it has been suggested that the Hippo pathway is involved in the development of resistance to KRAS inhibitors [37], and that combination with a TEAD inhibitor enhances the antitumor effect [38].”
Altered Mechanobiology of PDAC Cells with Acquired Chemoresistance to Gemcitabine and Paclitaxel
Gregori, A., Bergonzini, C., Capula, M., de Mercado, R. R., Danen, E. H. J., Giovannetti, E., & Schmidt, T. (2024) · Cancers · doi:10.3390/cancers16223863 · Cited by 6 · see citing works
“Moreover, YAP signaling was linked to chemoresistance to KRAS G12C inhibitors in non-small cell lung cancer [16,17].”
Sung, M., Huang, H.-E., Chang, Y.-C., Yu, C., Luo, H., & Sung, W. (2024) · Aging · doi:10.18632/aging.206076 · Cited by 5 · see citing works
Self-citationKumar, G., Khandibharad, S., & Singh, S. (2025) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2025.152727 · Cited by 5 · see citing works
Karaoğlanoğlu, S., & Gülbay, G. (2025) · Medicina · doi:10.3390/medicina61101835 · Cited by 5 · see citing works
“Studies have shown that cancer cells with KRAS mutations are often resistant to certain chemother-apies and targeted therapies [25].”
Wu, D., Zhu, C.-B., Pan, H., Xu, H., Xu, J., Liu, Y., Wang, S., Xiao, M.-M., Yu, X.-J., & Shi, S. (2026) · Gut · doi:10.1136/gutjnl-2025-336235 · Cited by 5 · see citing works
Self-citationIn Silico Identification of Dysregulated miRNAs Targeting KRAS Gene in Pancreatic Cancer
Garibaldi-Ríos, A. F., Figuera, L. E., Zúñiga‐González, G. M., Gómez‐Meda, B. C., García-Verdín, P. M., Carrillo-Dávila, I. A., Gutiérrez-Hurtado, I. A., Torres-Mendoza, B. M., & Gallegos‐Arreola, M. P. (2024) · Diseases · doi:10.3390/diseases12070152 · Cited by 5 · see citing works
“The above findings highlight the potential of miRNAs as biomarkers and possible therapeutic targets in the treatment of PC; however, experimental validation is needed to confirm these results.”
ResultExploring the Role of CBX3 as a Potential Therapeutic Target in Lung Cancer
Wahab, M. A., Gaudio, N. D., Gargiulo, B., Quagliariello, V., Maurea, N., Nebbioso, A., Altucci, L., & Conte, M. (2024) · Cancers · doi:10.3390/cancers16173026 · Cited by 5 · see citing works
“The Hippo pathway, which regulates organ size and suppresses tumors, often becomes dysregulated in NSCLC cells harboring KRAS mutations, particularly the KRAS G12C variant [69].”
BackgroundClinical Advances and Challenges in Targeting KRAS Mutations in Non-Small Cell Lung Cancer
Dekker, S. E., & Deng, L. (2024) · Cancers · doi:10.3390/cancers16223885 · Cited by 5 · see citing works
“Recent studies have demonstrated that Hippo (YAP/TAZ) signaling is a significant contributor to resistance against KRAS G12C inhibitors in vitro and in vivo [38,39].”
Aust, O., Thiel, M. R. T., Blanc, E., Lüthen, M., Hollek, V., Astaburuaga-García, R., Klinger, B., Böhning, F., Trinks, A., Beule, D., et al. (2025) · Science Signaling · doi:10.1126/scisignal.adr3738 · Cited by 4 · see citing works
Tolerance and Resistance to Targeted Therapy in NSCLC: Emerging Concepts and Strategies
Sanchez-Cespedes, M., Lockwood, W. W., Suda, K., Gardner, E. E., Mitsudomi, T., Politi, K., Rolfo, C., Sen, T., Sos, M. L., Tammela, T., et al. (2025) · JTO Clinical and Research Reports · doi:10.1016/j.jtocrr.2025.100944 · Cited by 4 · see citing works
“91 Furthermore, 40 sensitizing hits were shared across three cell lines and 31 resistance hits were shared across at least two lines.”
Hao, J., Zakershahrak, M., Ly, P., Le, A. D., Yu, W., Gates, J. C., & Chen, C. (2026) · Journal of Translational Medicine · doi:10.1186/s12967-026-07786-y · Cited by 5 · see citing works
“…has shown that YAP/TAZ activation can drive adaptive resistance to KRAS-pathway inhibition across multiple cancer types: in cells treated with KRAS G12C or G12D inhibitors, elevated YAP/TAZ activity reduces apoptosis and restores proliferation by reac-tivating downstream survival pathways [172].”
The Target Therapy Hyperbole: “KRAS (p.G12C)”—The Simplification of a Complex Biological Problem
Chetta, M., Basile, A., Tarsitano, M., Rivieccio, M., Oro, M., Capitanio, N., Bukvić, N., Priolo, M., & Rosati, A. (2024) · Cancers · doi:10.3390/cancers16132389 · Cited by 4 · see citing works
All Roads Lead to Rome: YAP/TAZ Activity Influences Efficacy of KRASG12C Inhibitors
Johnson, C. W., & Haigis, K. M. (2023) · Cancer Research · doi:10.1158/0008-5472.can-23-3547 · Cited by 4 · see citing works
Drivers of Pancreatic Cancer: Beyond the Big 4
Porcza, L. M., Ballesteros-Cillero, R., Lam, L. T., Maiello, C., & Leslie, N. R. (2025) · Cancers · doi:10.3390/cancers17142354 · Cited by 4 · see citing works
“The clinical significance of this is supported by data showing that Hippo pathway activation is able to bypass the dependence of PDAC on KRAS mutations and also drive resistance to KRAS G12C inhibitor therapy [127,128].”
An improved TEAD dominant-negative protein inhibitor to study Hippo YAP1/TAZ-dependent transcriptionPreprint
Branch, B., Yao Zong, Y. U. A. N., Cascone, M., Raimondi, F., & Iglesias‐Bartolomé, R. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.10.03.615022 · Cited by 4 · see citing works
Wang, J., Sun, W., Chen, X., Li, Y., Zhang, S., Jin, Y., Tian, X., & Du, Y. (2025) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2025.152372 · Cited by 3 · see citing works
Fu, W., Chang, N., Liang, H., Xu, R., Yang, K., Xu, L., & Wang, X. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-07191-x · Cited by 3 · see citing works
“Recent pioneering studies have successfully employed Genome-Wide CRISPR Screens to identify novel resistance markers in Non-small lung cancers [39].”
King, H. E., O’Connell, S., Kavanagh, D., Mason, S., McCool, C. S., Fernández-Chamorro, J., Chaffer, C. L., Clark, S. J., Vieira, H. G. S., Sterne-Weiler, T., et al. (2026) · Nucleic Acids Research · doi:10.1093/nar/gkag118 · Cited by 3 · see citing works
“This technology has uncovered complex cellular networks and mechanisms, ranging from basic biological processes [ 2 –4 ] to therapeutic applications [ 5 –8 ].”
Kumar, R., Thian, J., Toh, J. D. W., Mohideen, N. F., Sun, J., Kang, C., Low, S. M. C., Wee, S., Lim, Z., Gunaratne, J., et al. (2026) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.5c00590 · Cited by 3 · see citing works
Harnessing Tumor Mechanobiology in NSCLC Treatment
Papavassiliou, K. A., Gogou, V. A., & Papavassiliou, A. G. (2024) · Archivos de Bronconeumología · doi:10.1016/j.arbres.2024.04.001 · Cited by 3 · see citing works
Targeting undruggable protein KRAS for cancer therapy: novel opportunities and challenges
Yang, X., Li, X., Zhang, Y., Zhang, S., Zhang, M., Sun, C., Yang, L., Liu, H., & Yuan, S. (2024) · Future Medicinal Chemistry · doi:10.1080/17568919.2024.2444865 · Cited by 3 · see citing works
Cai, L., Wu, F., Zhou, Q., Gao, Y., Yao, B., DeBerardinis, R. J., Acquaah-Mensah, G. K., Aidinis, V., Beane, J., Biswal, S., et al. (2025) · Cancer Research · doi:10.1158/0008-5472.can-24-1607 · Cited by 2 · see citing works
Li, Q., Ma, C., Zuo, L., Xu, A., Zhang, B., Zhao, F., Liu, L., Zhao, X., Hu, Y., & Sun, C. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-07065-2 · Cited by 2 · see citing works
“Moreover, given that mutagenic KRAS activation upregulates the MMEJ pathway, Polθ is critical for KRAS-driven pancreatic tumorigenesis, suggesting a potential synthetic lethality approach by combining KRAS and Polθ inhibitors [43, 44].”
Rosen, J. C., Cao, P. M., Pham, N., Waas, M., Li, Q., Hueniken, K., Wang, M., Navab, R., Wybenga-Groot, L. E., Radulovich, N., et al. (2025) · British Journal of Cancer · doi:10.1038/s41416-025-03216-w · Cited by 2 · see citing works
Tumor suppressor genes and KRAS G12C inhibitor resistance in non-small cell lung cancer
Zhu, L., Jia, X., Xu, L., Chen, L., Fu, X., Yan, H., Ai, B., & Peng, S. (2025) · iScience · doi:10.1016/j.isci.2025.114429 · Cited by 2 · see citing works
“66 Preclinical studies show that compared to KEAP1 WT H358 cells, HCC44 cells (KRAS G12C, and LKB1/KEAP1-mutated) exhibited marked resistance to ARS-1620, a phenotype attributed to KEAP1/NRF2-mediated redox buffering rather than LKB1 loss.”
InfluentialMTHFD2 is required for DNA repair and implicated in LUAD radiotherapy resistance
Huang, Q., Ouyang, W., Su, S., Ma, Z., Hu, Y., Geng, Y., Chen, X., Li, Q. L., Yang, W., & Lu, B. (2026) · Journal of Translational Medicine · doi:10.1186/s12967-026-07680-7 · Cited by 2 · see citing works
Fibroblasts Promote Resistance to KRAS Silencing in Colorectal Cancer Cells
Mendonça, S., Carvalho, P. D., Serra‐Roma, A., Oliveira, P., Ribeiro, A., Carvalho, J., Martins, F., Machado, A. L., Oliveira, M. J., & Velho, S. (2024) · Cancers · doi:10.3390/cancers16142595 · Cited by 2 · see citing works
“KRAS-targeted inhibition (using inhibitors such as sotorasib or adagrasib) can also inadvertently activate Hippo signaling [62], which promotes the maintenance of EMT characteristics essential for cancer cells to overcome KRAS suppression and develop resistance against these inhibitors [60,62].”
BackgroundLiu, Y., Tu, Y., Yan, Z., Xiao, J., Zhou, B., Liu, T., Qi, L., Wu, D., Hu, Y., Cao, Y., et al. (2025) · Cancer Letters · doi:10.1016/j.canlet.2025.217688 · Cited by 2 · see citing works
Self-citationTang, Z., Ye, J., & Chen, D. (2025) · Journal of Biochemical and Molecular Toxicology · doi:10.1002/jbt.70271 · Cited by 2 · see citing works
“…of the mechanisms of these driver genes is reshaping the diagnosis and treatment of NSCLC, bringing new strategies for the clinical treatment of NSCLC. KRAS mutations are common genetic alterations in NSCLC, especially in adenocarcinoma patients, accounting for approximately 30% of cases [9].”
Nakagawa, R. M., Beardsley, A. R., Durney, S., Hayward, M.-K., Subramanyam, V., Meyer, N. P., Wismer, H., Goodarzi, H., Weaver, V. M., de Mark, D. V., et al. (2025) · eLife · doi:10.7554/elife.105719 · Cited by 2 · see citing works
The Phenotypical Characterization of Dual-Nature Hybrid Cells in Uveal Melanoma
Marcotte, E., Goyeneche, A. A., Abdouh, M., Burnier, J. V., & Burnier, M. N. (2024) · Cancers · doi:10.3390/cancers16183231 · Cited by 1 · see citing works
Elm, L., Gerlitz, N., Hochholzer, A., Papadopoulos, T., & Levidou, G. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26135938 · Cited by 1 · see citing works
“VT104 (also known as VT3989), an allosteric TEAD inhibitor targeting the TEAD lipid pocket, demonstrated strong preclinical efficacy in models of KRAS-mutant cancers and is currently undergoing clinical evaluation [63].”
Novel paradigms in KRAS targeting: Unveiling strategies to combat drug resistance
Luo, X., Zhou, F., Tang, Y., Liu, X., Xiao, R., Gu, M., Bai, J., Jiang, D., Yang, G., You, L., et al. (2025) · Chinese Medical Journal · doi:10.1097/cm9.0000000000003776 · Cited by 2 · see citing works
Targeting RAS for Cancer Treatment: What a Long, Strange Trip It's Been
Cox, A. D., & Der, C. J. (2025) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-071024-082459 · Cited by 1 · see citing works
Advances and Challenges in KRAS Mutation Detection and Clinical Implications
Mirlohi, M. S., Yousefi, T., Razaviyan, J., Nomiri, S., Pishbin, E., Shabani‐Rad, M., Ahmadian, M. R., & Salami, S. (2025) · Cancers · doi:10.3390/cancers18010031 · Cited by 1 · see citing works
“Additionally, emerging data support combining KRAS‑targeted agents with immune checkpoint inhibitors, particularly in tumors exhibiting adaptive immuno‑ suppression following KRAS inhibition [57,58].”
Li, Y., Chanda, D., Jeon, S.-W., Jeon, J., & Kim, M.-J. (2026) · Cancers · doi:10.3390/cancers18111786 · Cited by 1 · see citing works
“Genome-wide CRISPR screening analyses demonstrated that YAP/TAZ–TEAD pathway components represent synthetic-lethal vulnerabilities in the context of KRAS G12C inhibition, while KRAS inhibitor treatment itself may induce RHO/ROCK-dependent nuclear YAP activation [51].”
He, X., Chen, Z., Luo, J., Chen, H., Hou, Y., Liu, D., & Liu, Y. (2026) · Journal of Translational Medicine · doi:10.1186/s12967-026-08339-z · Cited by 1 · see citing works
“Furthermore, as acquired resistance often limits the long-term efficacy of direct targeted therapies (such as KRAS inhibitors), genome-wide CRISPR screens have underscored the critical need to identify targetable dependencies to enhance treatment responses [60].”
Self-citationGao, Y., Zhang, K., Li, W., Liu, J., Kwon, D., Gu, L., Li, A., Yin, H. H., Kowolik, C. M., Raul, M. C., et al. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27125561 · Cited by 1 · see citing works
“…that USP22 has been reported to stabilize YAP by preventing its degradation [16], inhibition of USP22 by β -Lapachone in KRAS-mutant lung cancer may attenuate YAP/TEAD signaling, which plays a crucial role in KRAS-mutant lung cancer stemness, growth, survival, and therapeutic resistance [50,51].”
Seraphine, C., MacLeod, A., Thornsberry, T., Dharmadhikari, S., Martinez, B., Gable, C., Chambers, A., Jaganathan, V. L., Littlefield, A., & Galandiuk, S. (2026) · Cancers · doi:10.3390/cancers18132049 · Cited by 1 · see citing works
“YAP/TEAD signaling has emerged as a critical bypass mechanism in the setting of KRAS inhibition, with YAP1/TAZ activation compensating for suppressed KRAS effector output by restoring ERK-independent transcription of proliferative genes and activating the PI3K–AKT–mTOR axis [95].”
Nakagawa, R. M., Beardsley, A. R., Durney, S., Hayward, M.-K., Subramanyam, V., Meyer, N. P., Wismer, H., Goodarzi, H., Weaver, V. M., de Mark, D. V., et al. (2025) · eLife · doi:10.7554/elife.105719.1 · Cited by 1 · see citing works
CRISPR Technology in Lung Diseases: The Example of Lung Cancer and Cystic Fibrosis
Porcel, J. M., Pont, M., & Sorolla, A. (2024) · Archivos de Bronconeumología · doi:10.1016/j.arbres.2024.04.017
Mediating kinase activity in Ras-mutant cancer: potential for an individualised approach?
Healy, F. M., Turner, A. L., Marensi, V., & MacEwan, D. J. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1441938
Nakagawa, R., Beardsley, A., Durney, S., Hayward, M.-K., Subramanyam, V., Meyer, N. P., Wismer, H., Goodarzi, H., Weaver, V., de Mark, D. V., et al. (2024) · bioRxiv · doi:10.1101/2024.09.26.615226 · Cited by 2 · see citing works
“Previous studies have implicated Yes-associated protein (YAP), a transcriptional co-activator that shuttles between the cytoplasm and nucleus in response to integrin signaling and biophysical stimuli (18–20), as a potential mediator of EGFRi and G12Ci resistance in NSCLC (21–24).”
BackgroundWang, Y., Manokaran, C., Huang, K. Y., Schaffhausen, B. S., & Roberts, T. M. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2426862122
“This represents an important question, especially because YAP/TAZ is involved in disease pathogenesis—such as notably, the acquisition of cancer cell resistance toward KRAS inhibition ( 41 – 43 ).”
Pei, Z., Zhang, Y., Xu, H., Pei, P., Zhang, Z., Wang, H., Zhang, B., Bai, J., Zhao, Y., Gu, J., et al. (2025) · Oncology Letters · doi:10.3892/ol.2025.15202
Ding, L., & Ding, Y. (2025) · medRxiv · doi:10.1101/2025.08.01.25332641
“The transcriptional co-activator YAP, upon Hippo pathway inactivation, complexes with TEAD to drive pro-survival and pro-proliferative genes, conferring resistance to targeted therapies and conventional treatments in NSCLC [28-29].”
Bhave, S. N., Das, S. R. C., & Prajapati, A. (2025) · IGI Global eBooks · doi:10.4018/979-8-3373-5796-6.ch004
Integrated multi-omics analysis reveals TMEM147 as an immunosuppressive prognostic biomarker in LUAD
Ding, L., & Ding, Y. (2025) · Biochemistry and Biophysics Reports · doi:10.1016/j.bbrep.2025.102281
“The transcriptional co-activator YAP, upon Hippo pathway inactivation, complexes with TEAD to drive pro-survival and pro-proliferative genes, conferring resistance to targeted therapies and conventional treatments in NSCLC [33,34].”
Yang, F., Duan, Y., Li, Y., Zhu, D., Wang, Z., Luo, Z., Zhang, Y., Zhang, G., He, X., & Kang, X. (2024) · Figshare · doi:10.6084/m9.figshare.26043665
Liu, M., Wu, S., Wu, H., Zhou, Y., Zhang, X., Zhu, D., & Jiang, J. (2024) · Figshare · doi:10.6084/m9.figshare.26726183
Liu, M., Wu, S., Wu, H., Zhou, Y., Zhang, X., Zhu, D., & Jiang, J. (2024) · Figshare · doi:10.6084/m9.figshare.26726189
Barua, A., Kundu, S. T., Garza, S., Fradette, J. J., Choudhary, B. S., Peng, D. H., Diao, L., Wang, J., & Gibbons, D. L. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.22.696060
“Currently, for NSCLC, it has been demonstrated that resistance to KRAS G12C inhibitors is a result of genetic mutations or amplification of either RAS genes 14,32 or genes like BRAF and MAP2K1, resulting in reactivation of the MAPK pathway 14,32,34,35 .”
InfluentialSensitization Strategies for Drug Therapy in KRAS-Mutant Colorectal Cancer
孟, 秋. (2026) · Advances in Clinical Medicine · doi:10.12677/acm.2026.162386
HDAC1-modified lamin A/C drives nuclear deformation in RB1-deficient lung adenocarcinoma
Li, H., Chen, Y., Wei, L., Wu, P., Fang, F., Li, F., Liu, B., Li, S., He, Q., Zhou, J., et al. (2026) · Lung Cancer · doi:10.1016/j.lungcan.2026.109301
Self-citationHe, H., Chuan, Z., Wang, C., Wang, J., Hu, H., Yang, J., & Zhou, F. (2026) · Cancers · doi:10.3390/cancers18050771 · Cited by 1 · see citing works
Self-citationMunshani, S., Ibrahim, E., Rodwin, R. L., Ferrucci, L. M., Blenman, K., Lustberg, M., & Ehrlich, B. E. (2026) · FEBS Open Bio · doi:10.1002/2211-5463.70239
CircPRKCA Promotes NSCLC Progression via miR-200b-3p/FRMD6/SNAI2 Axis
Zhong, H., Wang, N., Zhang, H., Chen, M., Liao, X., & Huang, C. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27093824
- Authors
- Mukhopadhyay, S., Huang, H.-Y., Lin, Z., Ranieri, M., Li, S., Sahu, S., Liu, Y., Ban, Y., Guidry, K., Hu, H., Lopez, A., Sherman, F., Tan, Y. J., Lee, Y. T., Armstrong, A. P., Dolgalev, I., Sahu, P., Zhang, T., Lu, W., Gray, N. S., Christensen, J. G., Tang, T. T., Velcheti, V., Khodadadi-Jamayran, A., Wong, K.-K., & Neel, B. G.
- Affiliations
- NYU Langone Health (US)
- New York University (US)
- Stanford Medicine (US)
- Mirati Therapeutics (United States) (US)
- 5Vivace Therapeutics, Inc., San Mateo, California.
- 2Applied Bioinformatics Laboratories, Office of Science and Research, New York University Grossman School of Medicine, New York, New York.
- Corresponding author
- Mukhopadhyay, Suman
- Wong, Kwok-Kin
- Neel, Benjamin G.
- ORCID
- Mukhopadhyay, Suman
- Huang, Hsin-Yi
- Lin, Ziyan
- Ranieri, Michela
- Li, Shuai
- Sahu, Soumyadip
- Liu, Yingzhuo
- Ban, Yi
- Guidry, Kayla
- Hu, Hai
- Lopez, Alfonso
- Sherman, Fiona
- Tan, Yi Jer
- Lee, Yeuan Ting
- Armstrong, Amanda P.
- Dolgalev, Igor
- Sahu, Priyanka
- Zhang, Tinghu
- Lu, Wenchao
- Gray, Nathanael S.
- Christensen, James G.
- Tang, Tracy T.
- Velcheti, Vamsidhar
- Khodadadi-Jamayran, Alireza
- Wong, Kwok-Kin
- Neel, Benjamin G.
- Venue
- Cancer Research
- Published
- 2023-09-20
- Volume
- 83
- Issue
- 24
- Pages
- 4095-4111
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC10841254
- OpenAlex
- W4386883000
- Semantic Scholar
- 2dfa2e52a2cd5ec3e9a68b8b970d810209dce28a
- Cited by
- 105
- References
- 77
- Citations by year
- 2026: 22 · 2025: 44 · 2024: 37 · 2023: 2
- FWCI
- 19.35
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (CA248896, P30CA016087, P41 EB017183)
- National Cancer Institute (5P30CA016087)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Keywords
- KRAS G12C, synthetic lethality, non-small cell lung cancer, adagrasib, SHP2 inhibitors, STK11, Keap1, RhoA activation, rocks, drug resistance, combination therapy, serine/threonine kinase, tRNA modification enzymes, proteoglycan synthesis
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Acetonitriles, Animals, Humans, Lung Neoplasms, Mutation, Piperazines, Pyrimidines, Proto-Oncogene Proteins p21(ras), Protein Serine-Threonine Kinases, NF-E2-Related Factor 2, Mice
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