The DOI matches its Crossref record; 76 of the 77 references it cites were found in a registry or an index; 3 of the 58 sources its claims cite were checked for support.
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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Claims the paper makes
65 Own result · 43 Not checked yet · 16 Own interpretation · 8 Own method · 2 No basis given · 1 Supported · 1 Partly supported · 1 Couldn’t confirm · accuracy not yet measured
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“Alternatively, or in addition, LKB1 activates DBL, a RHO-GEF(59).”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > DISCUSSION
What the sources say
- Could not verifycites [59] Mohseni, 2014, A genetic screen identifies an LKB1-MARK signalling axis controlling the Hippo-YAP pathway, Nat Cell Biol sourceExperimental — accuracy not yet measured
The main text (section labelled Abstract; page unavailable) says LKB1 affects the actin cytoskeleton but does not say it activates DBL. Reference 37 names a study of LKB1, Rho and its exchange factor Dbl; its title likewise does not establish DBL activation. Searches for DBL activation found no supporting passage in our copy. (LLM, conf=0.73)
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Could not verify
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Unsupervised clustering clearly separated control and treated groups in both lines”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > RHO Directs ROCK-Dependent Nuclear Localization of YAP in Response to MRTX-849
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Similar results were obtained with other NSCLC lines (H2122, H23) and with the PDAC cell line MiaPaca2”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > RHO Directs ROCK-Dependent Nuclear Localization of YAP in Response to MRTX-849
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > INTRODUCTION
plaindirectn = 4- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- 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.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“TEAD reporter activity increased by >6-fold in G12Ci-treated cells (Fig. 3A).”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > RHO Directs ROCK-Dependent Nuclear Localization of YAP in Response to MRTX-849
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“MRTX-849 treatment also increased levels of nuclear YAP in H2030 cells, beginning at 4 hours and peaking at 24-48 hours”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > RHO Directs ROCK-Dependent Nuclear Localization of YAP in Response to MRTX-849
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“transcript levels of the YAP/TEAD-inducible gene CYR61 were increased after 48h of MRTX-849 treatment in two NSCLC lines tested”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > RHO Directs ROCK-Dependent Nuclear Localization of YAP in Response to MRTX-849
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“SHOC2, a known SL gene in MEK-inhibitor treated cells (32), was depleted in 3/4 lines”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > Genome-Wide CRISPR/Cas9 Screens Identify G12Ci Synthetic Lethal Genes
What the sources say
- Not checked yetcites [32] Sulahian, 2019, Synthetic lethal interaction of SHOC2 depletion with MEK inhibition in RAS-driven cancers, Cell Rep source
plainn = 3- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Remarkably, many upregulated pathways, including Hippo Signaling, conformed to the SL pathways identified by our screen (compare Fig. 1E and 3C).”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > RHO Directs ROCK-Dependent Nuclear Localization of YAP in Response to MRTX-849
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“TEAD1 or WWTR1 depletion by siRNAs (“Smartpool”) or doxycycline-inducible shRNAs enhanced MRTX-849 efficacy in multiple lines”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > YAP1/TAZ/TEAD Inhibition Enhances Adagrasib Action
plaindirect- Asserted: passes — The authors put it forward as true.
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- Probably not a substantial claim. 36
- It may state two separate claims as one. 46
Every source the paper cites for this claim was checked and supports it.
In the paper
“YAP/TAZ pathway activation is also a known mechanism of resistance to other targeted therapies, including RAF V600E and MEK inhibitors (36).”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > YAP1/TAZ/TEAD Inhibition Enhances Adagrasib Action
What the sources say
- Supportedcites [36] Nguyen, 2019, YAP/TAZ signaling and resistance to cancer therapy, Trends Cancer source
The targeted-therapy section reports that YAP mediates resistance to BRAF inhibitors and MAPK inhibitors in BRAF-mutant cancer cells. It also discusses resistance to combined BRAF and MEK inhibition in BRAFV600E melanoma, supporting the citing sentence's characterization. (LLM, conf=0.93)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > TEAD Inhibitors Enhance The Efficacy of G12Ci in KRAS Mutant-Driven NSCLC
What the sources say
- Partly supportedcites [48] Fan, 2022, Covalent disruptor of YAP-TEAD association suppresses defective Hippo signaling, eLife sourceExperimental — accuracy not yet measured
The Results report covalent binding in the conserved TEAD palmitate pocket, reduced endogenous YAP–TEAD association, and inhibited YAP–TEAD transcriptional activity (Figures 2–4; page numbers unavailable). They establish irreversible inhibition of TEAD palmitoylation, not that disruption of YAP–TEAD association is irreversible. The TEAD1–4 assay measured palmitoylation; the transcriptional reporter did not establish inhibition of each paralog’s transcriptional activity separately. (LLM, conf=0.85)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > Genome-Wide CRISPR/Cas9 Screens Identify G12Ci Synthetic Lethal Genes
plainn = 3- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > YAP1/TAZ/TEAD Inhibition Enhances Adagrasib Action
What the sources say
- Not checked yetcites [38] Rosenbluh, 2012, beta-Catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis, Cell source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Others included potential novel, parallel targets, including DNA damage (Fanconi anemia pathway), heparan sulphate metabolism, glycosylation, and translation initiation pathways”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > Genome-Wide CRISPR/Cas9 Screens Identify G12Ci Synthetic Lethal Genes
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > Genome-Wide CRISPR/Cas9 Screens Identify G12Ci Synthetic Lethal Genes
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“including MAPK Family Signaling, PI3K/AKT/mTOR Signaling, FGF Signaling, PDGF Signaling, Autophagy, C-MYC Pathway and E2F targets.”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > Genome-Wide CRISPR/Cas9 Screens Identify G12Ci Synthetic Lethal Genes
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Enrichr analysis revealed SL pathways (p<0.05)shared in at least two lines, with most common to three or four (Fig. 1E).”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > Genome-Wide CRISPR/Cas9 Screens Identify G12Ci Synthetic Lethal Genes
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > Genome-Wide CRISPR/Cas9 Screens Identify G12Ci Synthetic Lethal Genes
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > TEAD Inhibitors Enhance The Efficacy of G12Ci in KRAS Mutant-Driven NSCLC
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > Validation of other shared SL genes from CRISPR/Cas9 screens
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Several genes were SL with single agent MRTX-849 and with MTRX-849/TNO-155 (indicated in red); others were unique to one treatment”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > Mechanisms of Resistance to G12C/SHP2 Co-Inhibition in RAS-Driven NSCLC
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Addition of SHP099 resulted in partial responses, but tumors resistant to both agents (Combo-resistant tumors) soon recurred”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > Resistance to G12Ci or G12Ci+SHP2i in Mouse and Human Induces Similar Pathways to Those Targeted by SL Genes
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Notably, TEAD and/or TAZ were also induced in RPPAs of nodules from MRTX-849/SHP099-treated mice”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > Resistance to G12Ci or G12Ci+SHP2i in Mouse and Human Induces Similar Pathways to Those Targeted by SL Genes
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Importantly, Hippo and RHO GTPase signaling genes were enriched in both resistant tumors, along with glycolysis, MYC, glycosylation and mTOR signaling genes.”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > Resistance to G12Ci or G12Ci+SHP2i in Mouse and Human Induces Similar Pathways to Those Targeted by SL Genes
plaincorrelationaln = 2- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > Mechanisms of Resistance to G12C/SHP2 Co-Inhibition in RAS-Driven NSCLC
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Some malignant cells remain, however, because after drug withdrawal, tumors recur.”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > TEAD Inhibitors Enhance The Efficacy of G12Ci in KRAS Mutant-Driven NSCLC
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > Mechanisms of Resistance to G12C/SHP2 Co-Inhibition in RAS-Driven NSCLC
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > DISCUSSION
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > TEAD Inhibitors Enhance The Efficacy of G12Ci in KRAS Mutant-Driven NSCLC
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“VRK1, ELP3, and ELP5 expression were significantly increased in the AMG-510-resistant patient sample, while RIOK2 levels were nominally increased (Supplementary Table S10).”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > DISCUSSION
plaincorrelationalSingle case- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Also stated in: § STATEMENT OF SIGNIFICANCE · plain
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“By contrast, VRK2 is expressed in NSCLC.”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we also validated two kinases (VRK1, RIOK2) and two tRNA-modifying enzymes (ELP3, ELP5) that scored as G12Ci SL genes.”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > DISCUSSION
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > INTRODUCTION
What the sources say
- Not checked yetcites [10] Janne, 2022, Adagrasib in non-small-cell lung cancer harboring a KRAS(G12C) mutation, N Engl J Med source
- Not checked yetcites [12] Skoulidis, 2021, Sotorasib for lung cancers with KRAS p.G12C mutation, N Engl J Med source
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > INTRODUCTION
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > INTRODUCTION
What the sources say
- Not checked yetcites [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 yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“RHO/ROCK signaling can promote YAP activation; also, Rhoa is required for mutant Kras-induced NSCLC in mice (42).”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > RHO Directs ROCK-Dependent Nuclear Localization of YAP in Response to MRTX-849
What the sources say
- Not checked yetcites [42] Konstantinidou, 2013, RHOA-FAK is a required signaling axis for the maintenance of KRAS-driven lung adenocarcinomas, Cancer Discov source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > INTRODUCTION
What the sources say
- Not checked yetcites [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 yetcites [15] Ryan, 2022, KRAS(G12C)-independent feedback activation of wild-type RAS constrains KRAS(G12C) inhibitor efficacy, Cell Rep source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Mutations in KRAS drive 25-30% of NSCLC cases (1)(2)(3); approximately half of these mutations convert glycine 12 to cysteine (G12C).”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > INTRODUCTION
What the sources say
- Not checked yetcites (1)(2)(3)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > INTRODUCTION
What the sources say
- Not checked yetcites [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 yetcites [10] Janne, 2022, Adagrasib in non-small-cell lung cancer harboring a KRAS(G12C) mutation, N Engl J Med source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > YAP1/TAZ/TEAD Inhibition Enhances Adagrasib Action
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“TEAD inhibitors are in clinical trials for NF2-mutant mesothelioma and other indications (e.g., NCT05228015 and NCT04665206) (35).”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > YAP1/TAZ/TEAD Inhibition Enhances Adagrasib Action
What the sources say
- Not checked yetcites [35] Pobbati, 2023, Therapeutic targeting of TEAD transcription factors in cancer, Trends Biochem Sci source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“We and others reported previously that SHP2 inhibition enhances G12Ci action in vitro and in mice (16,45,46)”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > Mechanisms of Resistance to G12C/SHP2 Co-Inhibition in RAS-Driven NSCLC
What the sources say
- Not checked yetcites [16] Fedele, 2021, SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling, J Exp Med source
- Not checked yetcites [45] Ryan, 2020, Vertical pathway inhibition overcomes adaptive feedback resistance to KRAS(G12C) inhibition, Clin Cancer Res source
- Not checked yetcites [46] Ahmed, 2019, SHP2 drives adaptive resistance to ERK signaling inhibition in molecularly defined subsets of ERK-dependent tumors, Cell Rep source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“previous work showed that LKB1 (encoded by STK11) antagonizes YAP activation by activating a PAR1->Scribble->MST2->LATs pathway”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > DISCUSSION
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > RHO Directs ROCK-Dependent Nuclear Localization of YAP in Response to MRTX-849
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > Genetically Engineered Mouse Model (GEMM) Generation and Treatment
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“They reported that G12Ci treatment induces Scribble mislocalization, which leads to decreased MST2/LATS suppression of YAP nuclear localizaton.”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“which dampen YAP activation in STK11-deficient cells and help explain this apparent paradox.”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > DISCUSSION
What the sources say
- Not checked yetcites [40] Franklin, 2023, Insights into recent findings and clinical application of YAP and TAZ in cancer, Nat Rev Cancer source
- Not checked yetcites [41] Piccolo, 2023, YAP/TAZ as master regulators in cancer: modulation, function and therapeutic approaches, Nat Cancer
- Not checked yetcites [36] Nguyen, 2019, YAP/TAZ signaling and resistance to cancer therapy, Trends Cancer source
- Not checked yetcites [55] Han, 2020, CRISPR screens in cancer spheroids identify 3D growth-specific vulnerabilities, Nature source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“VT-104 is a clinical grade, non-covalent, pan-TEAD inhibitor that also binds this pocket.”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > TEAD Inhibitors Enhance The Efficacy of G12Ci in KRAS Mutant-Driven NSCLC
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“preliminary results indicate that at least one, VT3989, is safe with manageable toxicity (19).”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > DISCUSSION
What the sources say
- Not checked yetcites [19] Olivieri, 2021, Genome-scale chemogenomic CRISPR screens in human cells using the TKOv3 library, STAR Protoc source
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Other TEAD inhibitors are already in phase 1 clinical trials (NCT05228015 and NCT04665206)”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > DISCUSSION
What the sources say
- Not checked yetcites NCT05228015
- Not checked yetcites NCT04665206
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Hagenbeek et al. (56) reported the development of allosteric TEAD inhibitors and demonstrated their ability to block adaptive resistance to G12Ci treatment”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > DISCUSSION
What the sources say
- Not checked yetcites [56] Dey, 2020, Targeting the Hippo pathway in cancer, fibrosis, wound healing and regenerative medicine, Nat Rev Drug Discov source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Adachi et al. also observed G12Ci-induced YAP translocation in STK11-replete H358 cells and in LU65 cells, which are STK11-/-”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Adachi et al. (57) found similar effects of YAP1 deficiency in a limited number of NSCLC lines and H358 xenografts.”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > DISCUSSION
What the sources say
- Not checked yetcites [57] Hagenbeek, 2023, An allosteric pan-TEAD inhibitor blocks oncogenic YAP/TAZ signaling and overcomes KRAS G12C inhibitor resistance, Nat Cancer source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Lines were tested for mycoplasma contamination by PCR 5-7 days after thawing.”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > Cell Lines and Reagents
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“multiple SHP2i are in clinical trials for KRAS G12C -mutant tumors and other indications (e.g., NCT05480865, NCT03565003, NCT04916236, NCT04699188) (47).”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > Mechanisms of Resistance to G12C/SHP2 Co-Inhibition in RAS-Driven NSCLC
What the sources say
- Not checked yetcites [47] Kerr, 2021, Allosteric SHP2 inhibitors in cancer: Targeting the intersection of RAS, resistance, and the immune microenvironment, Curr Opin Chem Biol source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > Genetically Engineered Mouse Model (GEMM) Generation and Treatment
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Significance was set at P = 0.05 for all analyses except screen data, where genes with FDR<0.1 were considered for further analysis.”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > Statistical Analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“YAP localization in cell populations was quantified by two double-blinded observers.”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > Immunofluorescence
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > scRNA-Seq of Patient Samples
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The existence of multiple G12Ci resistance mechanisms indicates that combination therapies will be required to maximize the impact of these remarkable drugs.”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > DISCUSSION
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence.
- Rests on an assumption: KRAS G12C inhibitors have so far produced only modest efficacy in the clinic.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results suggest that TEAD inhibition could augment this drug combination as well as single agent MRTX-849.”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > Mechanisms of Resistance to G12C/SHP2 Co-Inhibition in RAS-Driven NSCLC
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“VRK1 was previously reported as a “collateral lethality” in glioblastoma, owing to methylation and lack of expression of its paralog VRK2 in this malignancy.”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“RHO, acting though the actomyosin cytoskeleton, is also known to promote YAP activation (40,41).”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > DISCUSSION
What the sources say
- Not checked yetcites [40] Franklin, 2023, Insights into recent findings and clinical application of YAP and TAZ in cancer, Nat Rev Cancer source
- Not checked yetcites [41] Piccolo, 2023, YAP/TAZ as master regulators in cancer: modulation, function and therapeutic approaches, Nat Cancer
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“and for Kras G12D -driven lung adenocarcinoma (42)”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > DISCUSSION
What the sources say
- Not checked yetcites [42] Konstantinidou, 2013, RHOA-FAK is a required signaling axis for the maintenance of KRAS-driven lung adenocarcinomas, Cancer Discov source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“earlier work found that RHOA is necessary for the transformation induced by mutant KRAS (60)(61)(62)”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > DISCUSSION
What the sources say
- Not checked yetcites [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 yetcites [61] Khosravi-Far, 1995, Activation of Rac1, RhoA, and mitogen-activated protein kinases is required for Ras transformation, Mol Cell Biol source
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“STK11 is also a critical regulator of metabolism via its substrate AMPK (73).”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > DISCUSSION
What the sources say
- Not checked yetcites [73] Mukhopadhyay, 2021, The metabolic landscape of RAS-driven cancers from biology to therapy, Nat Cancer source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“VRK1 depletion in these VRK2-deficient cells levels leads to a G2/M phase arrest, followed by DNA damage (67,68).”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > DISCUSSION
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Mutant KRAS is a well known regulator of glycolysis (72)”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > DISCUSSION
What the sources say
- Not checked yetcites [72] Cruz-Gordillo, 2020, ELP-dependent expression of MCL1 promotes resistance to EGFR inhibition in triple-negative breast cancer cells, Sci Signal source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Previous research showed that suppression of ELP1 or ELP3 can abrogate vemurafenib in BRAF V600E melanoma (70)”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > DISCUSSION
What the sources say
- Not checked yetcites [70] Cerezo, 2021, RIOK2 phosphorylation by RSK promotes synthesis of the human small ribosomal subunit, PLoS Genet source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“ROCK inhibitors are not associated with proteinuria, and thus could avoid the major drug-related side effect of TEAD inhibition (65).”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > DISCUSSION
What the sources say
- Not checked yetcites [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
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“RIOK2 is a relatively unexplored RSK target whose normal function is to promote maturation of the 40S ribosome (69).”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > DISCUSSION
What the sources say
- Not checked yetcites [69] So, 2022, VRK1 as a synthetic lethal target in VRK2 promoter-methylated cancers of the nervous system, JCI Insight source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“and that ELPs contribute to EGFR inhibitor resistance in breast cancer cells by promoting MCL1 synthesis (71).”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > DISCUSSION
What the sources say
- Not checked yetcites [71] Rapino, 2018, Codon-specific translation reprogramming promotes resistance to targeted therapy, Nature source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“previous studies have revealed complex, bidirectional interplay between the Hippo pathway and glucose metabolism (74).”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > DISCUSSION
What the sources say
- Not checked yetcites [74] Shackelford, 2009, The LKB1-AMPK pathway: metabolism and growth control in tumour suppression, Nat Rev Cancer source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“VRK1 must have specific functions in G12Ci-treated NSCLC cells.”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
- 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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredIn the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > TEAD Inhibitors Enhance The Efficacy of G12Ci in KRAS Mutant-Driven NSCLC
“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”
§ Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS G12C Inhibitor Efficacy > STATEMENT OF SIGNIFICANCE
“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.”
Citations
Cites
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625
featureCounts: an efficient general purpose program for assigning sequence reads to genomic features
Liao, Y., Smyth, G. K., & Shi, W. (2014) · Bioinformatics · doi:10.1093/bioinformatics/btt656 · Cited by 27,219
Metascape provides a biologist-oriented resource for the analysis of systems-level datasets
Zhou, Y., Zhou, B., Pache, L., Chang, M., Khodabakhshi, A. H., Tanaseichuk, O., Benner, C., & Chanda, S. K. (2019) · Nature Communications · doi:10.1038/s41467-019-09234-6 · Cited by 14,611
Enrichr: a comprehensive gene set enrichment analysis web server 2016 update
Kuleshov, M. V., Jones, M. R., Rouillard, A. D., Fernandez, N. F., Duan, Q., Wang, Z., Koplev, S., Jenkins, S. L., Jagodnik, K. M., Lachmann, A., et al. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw377 · Cited by 10,799
Genomic analyses identify molecular subtypes of pancreatic cancer
Bailey, P., Chang, D. K., Nones, K., Johns, A. L., Patch, A.-M., Gingras, M.-C., Miller, D. K., Christ, A. N., Bruxner, T. J. C., Quinn, M. C., et al. (2016) · Nature · doi:10.1038/nature16965 · Cited by 3,621
Li, W., Xu, H., Xiao, T., Cong, L., Love, M. I., Zhang, F., Irizarry, R. A., Liu, J. S., Brown, M., & Liu, X. S. (2014) · Genome Biology · doi:10.1186/s13059-014-0554-4 · Cited by 2,684
TEAD mediates YAP-dependent gene induction and growth control
Zhao, B., Ye, X., Yu, J., Li, L., Li, W., Li, S., Yu, J., Lin, J. D., Wang, C.-Y., Chinnaiyan, A. M., et al. (2008) · Genes & Development · doi:10.1101/gad.1664408 · Cited by 2,498
Self-citationHippo pathway in organ size control, tissue homeostasis, and cancer
Yu, F.-X., Zhao, B., & Guan, K.-L. (2015) · Cell · doi:10.1016/j.cell.2015.10.044 · Cited by 2,206
The LKB1-AMPK pathway: metabolism and growth control in tumour suppression
Shackelford, D. B., & Shaw, R. J. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2676 · Cited by 1,943
Sotorasib for Lung Cancers with KRAS p.G12C Mutation
Skoulidis, F., Li, B. T., Dy, G. K., Price, T. J., Falchook, G. S., Wolf, J., Italiano, A., Schuler, M., Borghaei, H., Barlesi, F., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2103695 · Cited by 1,849
Self-citation
Cited by
Sorted by citations
Singhal, A., Li, B. T., & O'Reilly, E. M. (2024) · Nature Medicine · doi:10.1038/s41591-024-02903-0 · Cited by 380
KRAS inhibitors: resistance drivers and combinatorial strategies
Isermann, T., Sers, C., Der, C. J., & Papke, B. (2024) · Trends in cancer · doi:10.1016/j.trecan.2024.11.009 · Cited by 217
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
Self-citationDetermining the ERK-regulated phosphoproteome driving KRAS-mutant cancer
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
YAP/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 91
Self-citation
Metadata
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-06, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-06 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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