The DOI matches its Crossref record; 54 of the 54 references it cites were found in a registry or an index; 53 of the 69 sources its claims cite were checked for support.
Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition
Published version of a preprint
Abstract
Abstract Purpose: Although KRAS represents the most commonly mutated oncogene, it has long been considered an “undruggable” target. Novel covalent inhibitors selective for the KRASG12C mutation offer the unprecedented opportunity to target KRAS directly. However, prior efforts to target the RAS–MAPK pathway have been hampered by adaptive feedback, which drives pathway reactivation and resistance. Experimental Design: A panel of KRASG12C cell lines were treated with the KRASG12C inhibitors ARS-1620 and AMG 510 to assess effects on signaling and viability. Isoform-specific pulldown of activated GTP-bound RAS was performed to evaluate effects on the activity of specific RAS isoforms over time following treatment. RTK inhibitors, SHP2 inhibitors, and MEK/ERK inhibitors were assessed in combination with KRASG12C inhibitors in vitro and in vivo as potential strategies to overcome resistance and enhance efficacy. Results: We observed rapid adaptive RAS pathway feedback reactivation following KRASG12C inhibition in the majority of KRASG12C models, driven by RTK-mediated activation of wild-type RAS, which cannot be inhibited by G12C-specific inhibitors. Importantly, multiple RTKs can mediate feedback, with no single RTK appearing critical across all KRASG12C models. However, coinhibition of SHP2, which mediates signaling from multiple RTKs to RAS, abrogated feedback reactivation more universally, and combined KRASG12C/SHP2 inhibition drove sustained RAS pathway suppression and improved efficacy in vitro and in vivo. Conclusions: These data identify feedback reactivation of wild-type RAS as a key mechanism of adaptive resistance to KRASG12C inhibitors and highlight the potential importance of vertical inhibition strategies to enhance the clinical efficacy of KRASG12C inhibitors. See related commentary by Yaeger and Solit, p. 1538
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59 Own result · 38 Own interpretation · 14 Partly supported · 7 No full text of the sources · 4 Supported · 2 Supported so far · 2 Not checked yet · 2 No basis given · 1 Own method · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“BRAF inhibition in BRAFV600 mutant cancers leads to loss of negative feedback signals regulated by the MAPK pathway, leading to receptor tyrosine kinase (RTK)-mediated reactivation of MAPK signaling through wild type RAS and RAF, particularly in specific tumor types, such as colorectal cancer (9–12).”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > INTRODUCTION
What the sources say
- Partly supportedcites [9] Paraiso, 2010, Recovery of phospho-ERK activity allows melanoma cells to escape from BRAF inhibitor therapy, Br J Cancer sourceExperimental — accuracy not yet measured
The Abstract Results report rapid recovery of phospho-ERK signaling after BRAF inhibition in melanoma cells. The Discussion suggests that pathway blockade may relieve feedback inhibition and cites prior work on signaling shifting from BRAF to CRAF. It does not establish RTK-mediated reactivation through wild-type RAS and RAF or a particular effect in colorectal cancer; those mechanisms and the broader tumor-type claim go beyond this paper. (LLM, conf=0.88)
- Supportedcites [10] Montero-Conde, 2013, Relief of feedback inhibition of HER3 transcription by RAF and MEK inhibitors attenuates their antitumor effects in BRAF-mutant thyroid carcinomas, Cancer Discov sourceExperimental — accuracy not yet measured
The Results describe increased RAS activity after RAF inhibition in BRAF-mutant thyroid cells, consistent with relief of upstream negative feedback. The Discussion links pathway rebound to RTK activation and signaling through wild-type RAF proteins; the Abstract and Discussion also report transient MAPK inhibition and EGFR-linked resistance in colorectal cancer cells. The paper’s direct mechanistic experiments concern thyroid cells, while its colorectal point is reported from other work. (LLM, conf=0.86)
- Partly supportedcites [11] Corcoran, 2012, EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib, Cancer Discov sourceExperimental — accuracy not yet measured
The Results and Discussion (page unavailable) support EGFR-mediated reactivation of RAS, CRAF and MAPK signaling after vemurafenib treatment in BRAF-mutant colorectal cancer. The citing sentence also presents loss of MAPK-regulated negative feedback as the cause; the Discussion offers that mechanism as a possibility and says further study is needed to establish it. The paper does not explicitly establish that the RAS and RAF involved are wild type. (LLM, conf=0.87)
- Partly supportedcites [12] Prahallad, 2012, Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR, Nature sourceExperimental — accuracy not yet measured
The ‘feedback activation of EGFR’ section reports that BRAF inhibition activates EGFR in BRAF-mutant colorectal cancer cells, and that adding an EGFR inhibitor produces more complete MEK and ERK inhibition. It describes feedback involving MEK, ERK and CDC25C, but does not establish that MAPK signaling is reactivated through wild-type RAS and RAF. (LLM, conf=0.86)
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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“These inhibitors undergo an irreversible reaction with the mutant cysteine present only in G12C mutant KRAS, making them highly selective for KRASG12C versus wild type KRAS or other RAS isoforms.”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > INTRODUCTION
What the sources say
- Not checked — no full text of the sourcecites [3] Patricelli, 2016, Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state, Cancer Discov source
- Supportedcites [4] Janes, 2018, Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor, Cell source
The Results report that ARS-1620’s activity was selective for KRASG12C rather than wild-type KRAS or other tested KRAS alleles, and attribute that specificity to covalent modification of Cys-12. The Introduction and Discussion also describe this inhibitor class as covalent and mutant-allele-specific, supporting the citing sentence’s account of its selectivity. (LLM, conf=0.88)
- Partly supportedcites [5] Fell, 2018, Discovery of tetrahydropyridopyrimidines as irreversible covalent inhibitors of KRAS-G12C with in vivo activity, ACS Med Chem Lett sourceExperimental — accuracy not yet measured
The passage labeled Abstract (page unavailable) reports that compound 13 was inactive in two wild-type KRAS cell lines and one KRAS-G12D cell line, supporting selectivity for KRAS-G12C over those comparators. It does not report testing against other RAS isoforms, so that part of the claim is not established by this paper. (LLM, conf=0.85)
boosteddirect- 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.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“in KRAS mutant cancers, MEK inhibitor treatment leads to adaptive feedback activation of RAS signaling, often through EGFR or other human epidermal growth factor receptor (HER) family members or FGFR, limiting efficacy (13,14).”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > INTRODUCTION
What the sources say
- Partly supportedcites [13] Manchado, 2016, A combinatorial strategy for treating KRAS-mutant lung cancer, Nature sourceExperimental — accuracy not yet measured
The “FGFR1 mediates adaptive drug resistance” section reports that trametinib increased FGFR1 signaling and RAS-GTP in KRAS-mutant lung cancer cells, supporting feedback activation that limits treatment efficacy. But the “FGFR1 inhibition enhances trametinib effects” section reports no increase in EGFR in the tested cells and only limited combinatorial activity for an EGFR/ERBB2 inhibitor. The paper therefore does not support the claim that EGFR or other HER family members are often the route of this response across KRAS-mutant cancers. Page numbers are not provided in our copy. (LLM, conf=0.86)
- Partly supportedcites [14] Kitai, 2016, Epithelial-to-mesenchymal transition defines feedback activation of receptor tyrosine kinase signaling induced by MEK inhibition in KRAS-mutant lung cancer, Cancer Discov sourceExperimental — accuracy not yet measured
The Results and Discussion report that MEK inhibition triggers feedback activation of ERBB3 or FGFR1 signaling in different subsets of KRAS-mutant lung cancer, reactivating MAPK/ERK signaling and contributing to resistance. The claim extends this finding to KRAS-mutant cancers generally and names EGFR as a route; this paper’s EGFR feedback example concerns BRAF-inhibited colorectal cancer, not MEK-inhibited KRAS-mutant cancer. The paper primarily demonstrates reactivation of downstream MAPK/ERK signaling rather than RAS signaling itself. (LLM, conf=0.86)
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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“early preclinical studies with KRASG12C inhibitors, such as ARS-1620, have suggested a potential role for adaptive feedback as a mechanism of resistance (7) (15).”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > INTRODUCTION
What the sources say
- Partly supportedcites [7] Lito, 2016, Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism, Science sourceExperimental — accuracy not yet measured
The paper’s indexed text (section labeled Abstract; page unavailable) reports that feedback-related RTK activation attenuated the inhibitory effect of ARS853 and suggests ways resistance to this class of drugs might emerge. It studies ARS853, not the cited example ARS-1620, so it does not directly support the claim for that compound. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites [15] Misale, 2019, KRAS G12C NSCLC models are sensitive to direct targeting of KRAS in combination with PI3K inhibition, Clin Cancer Res 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.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“However, preclinical and clinical data have demonstrated that other RTKs can drive feedback in an EGFR-independent manner”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > DISCUSSION
What the sources say
- Supportedcites [34] Corcoran, 2018, Combined BRAF, EGFR, and MEK inhibition in patients with BRAFV600E-mutant colorectal cancer, Cancer Discov source
The Discussion (page not supplied) reports EGFR-independent MAPK reactivation in patient biopsies and identifies CRC cell lines in which RTKs other than EGFR, such as MET, drive reactivation and resistance. It concludes that both EGFR-dependent and EGFR-independent feedback signals need to be inhibited in BRAF V600E-mutant colorectal cancer. (LLM, conf=0.93)
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.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“This finding is consistent with prior studies identifying HER family and FGFR signaling as key mediators of adaptive feedback to RAS-MAPK pathway inhibitors (10–14,21,22) and recent functional genomic screens(40).”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > DISCUSSION
What the sources say
- Partly supportedcites [10] Montero-Conde, 2013, Relief of feedback inhibition of HER3 transcription by RAF and MEK inhibitors attenuates their antitumor effects in BRAF-mutant thyroid carcinomas, Cancer Discov sourceExperimental — accuracy not yet measured
The Results and Discussion (page unavailable) identify HER2/HER3 signaling as a mediator of rebound signaling and reduced response to RAF or MEK inhibitors in BRAF-mutant thyroid cancer cells. Our copy does not identify FGFR signaling as a mediator; searches for “FGFR” and “fibroblast growth factor” found no supporting passage. The paper also emphasizes that the relevant reactivated receptors vary by cell type. (LLM, conf=0.90)
- Partly supportedcites [11] Corcoran, 2012, EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib, Cancer Discov sourceExperimental — accuracy not yet measured
The Results (page not provided) identify EGFR, a HER-family receptor, as the predominant mediator of MAPK reactivation after RAF inhibition in BRAF-mutant colorectal cancer cells. The Discussion (page not provided) describes a possible feedback mechanism but says it remains unproven. Our copy does not establish FGFR signaling as a mediator, so it supports only the EGFR portion of the broader claim. (LLM, conf=0.88)
- Partly supportedcites [12] Prahallad, 2012, Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR, Nature sourceExperimental — accuracy not yet measured
The “feedback activation of EGFR” section reports that BRAF or MEK inhibition activates EGFR, a HER-family receptor, in BRAF-mutant colorectal cancer cells. It does not establish FGFR signaling as a mediator, and its findings are narrower than a general claim about HER-family and FGFR responses to RAS–MAPK inhibitors. (LLM, conf=0.87)
- Partly supportedcites [13] Manchado, 2016, A combinatorial strategy for treating KRAS-mutant lung cancer, Nature sourceExperimental — accuracy not yet measured
The Discussion identifies FGFR1 feedback activation as a prominent mechanism of resistance to the MEK inhibitor trametinib in KRAS-mutant lung cancer. The “FGFR1 inhibition enhances trametinib effects” section reports some combinatorial activity for an EGFR/ERBB2 inhibitor, but does not establish HER-family signaling as a key mediator in this setting. The claim also generalizes beyond the specific inhibitor and cancer contexts examined. (LLM, conf=0.87)
- Supportedcites [14] Kitai, 2016, Epithelial-to-mesenchymal transition defines feedback activation of receptor tyrosine kinase signaling induced by MEK inhibition in KRAS-mutant lung cancer, Cancer Discov source
The Introduction reports that MEK inhibition activates ERBB3 signaling in epithelial-like KRAS-mutant lung cancer cells and FGFR1 signaling in mesenchymal-like cells. The Discussion identifies these as distinct feedback mechanisms that reactivate MAPK signaling. This supports the cited paper as an example of HER-family and FGFR-mediated adaptive feedback to a RAS–MAPK pathway inhibitor. (LLM, conf=0.90)
- Partly supportedcites [21] Sun, 2014, Intrinsic resistance to MEK inhibition in KRAS mutant lung and colon cancer through transcriptional induction of ERBB3, Cell Rep sourceExperimental — accuracy not yet measured
The Discussion (page not provided) reports that MEK inhibition upregulates ERBB2 and ERBB3, forming active HER-family complexes that sustain downstream signaling. This supports the HER-family part of the claim in KRAS-mutant lung and colon cancer, but our copy does not identify FGFR signaling as a mediator of this feedback. (LLM, conf=0.86)
- Partly supportedcites [22] Johnson, 2014, Molecular pathways: adaptive kinome reprogramming in response to targeted inhibition of the BRAF-MEK-ERK pathway in cancer, Clin Cancer Res sourceExperimental — accuracy not yet measured
Clinical-Translational Advances (page unavailable) describes receptor tyrosine kinase upregulation as an adaptive response to MEK inhibition, and Concluding Remarks gives a HER-family-targeting combination as an example. The copy does not identify FGFR signaling as a mediator of that feedback, so it supports only part of the attributed claim. (LLM, conf=0.86)
- Supportedcites [40] Lou, 2019, KRAS(G12C) inhibition produces a driver-limited state revealing collateral dependencies, Sci Signal source
The citation is attached specifically to “recent functional genomic screens,” and this paper reports genome-scale CRISPRi screens in KRASG12C-inhibited NSCLC and PDAC cells (Results, “Genome-scale CRISPRi screens nominate KRASG12C collateral dependent genes”; page unavailable). Its Results also identify EGFR and FGFR1 as cell-specific dependencies in those models. The citation therefore supports the cited example of a functional genomic screen, rather than a claim that both pathways mediate feedback in every RAS–MAPK inhibitor setting. (LLM, conf=0.90)
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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“First, as described by Lito et al, increased RTK activity may lead to increased cycling of KRASG12C to its active GTP-bound form that hinders the binding of most KRASG12C inhibitors, which bind specifically to the inactive GDP-bound form (7).”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > DISCUSSION
What the sources say
- Partly supportedcites [7] Lito, 2016, Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism, Science sourceExperimental — accuracy not yet measured
In the supplied copy (section labeled Abstract; no page given), Lito et al. report that RTK-mediated nucleotide exchange affects inhibition and that increased exchange lowers the GDP-bound KRASG12C available for ARS853 binding. This supports the proposed mechanism for ARS853, but the paper does not establish that most KRASG12C inhibitors bind specifically to the GDP-bound form. (LLM, conf=0.88)
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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“SHP2 acts to dephosphorylate and activate multiple nodes of RAS signaling downstream of RTKs, enhancing signaling through the RAS-RAF-MEK-ERK cascade (25–28).”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > RESULTS > SHP2 inhibition reduces feedback reactivation in response to KRASG12C inhibitors
What the sources say
- Partly supportedcites [25] Nichols, 2018, RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers, Nat Cell Biol sourceExperimental — accuracy not yet measured
The Introduction describes SHP2 as a phosphatase and scaffold downstream of RTKs that promotes RAS activation. The Results and Discussion link SHP2 to RAS-GTP loading and downstream RAS/MAPK signaling through adaptor-protein interactions and membrane recruitment. They do not establish that SHP2 dephosphorylates and activates multiple RAS-signaling nodes, so that specific mechanism is unsupported. (LLM, conf=0.86)
- Partly supportedcites [26] Frankson, 2017, Therapeutic targeting of oncogenic tyrosine phosphatases, Cancer Res sourceExperimental — accuracy not yet measured
In “SHP2 Is a Bona Fide Oncoprotein” (page not available), the paper says SHP2 is required for full Ras/ERK1/2 activation and describes several sites whose dephosphorylation can promote that signaling, including Ras itself. But it presents the mechanisms involving several sites as current models and says they remain under investigation; the claim states them as established and specifies RAF and MEK, which the cited passage does not discuss. (LLM, conf=0.84)
- Partly supportedcites [27] Mainardi, 2018, SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo, Nat Med sourceExperimental — accuracy not yet measured
The main text (lines 35–37 and 58–60; page not provided) describes SHP2 as linking RTK signaling to the RAS-RAF-MEK-ERK pathway and says increased RTK signaling activates that pathway through SHP2. It does not say that SHP2 dephosphorylates and activates multiple nodes of RAS signaling; that specific mechanism is unsupported by the cited passages. (LLM, conf=0.85)
- Partly supportedcites [28] Ruess, 2018, Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase, Nat Med sourceExperimental — accuracy not yet measured
The introduction (lines 37–40, 63–64; page not specified) describes SHP2 as a phosphatase involved in signaling downstream of receptors and says it promotes RAS–RAF–MEK–ERK signaling. The results (lines 168–175; page not specified) show that SHP2 phosphatase activity is required to restore MAPK signaling after MEK inhibition. Our copy does not identify multiple RAS-signaling nodes that SHP2 dephosphorylates and activates. (LLM, conf=0.86)
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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Indeed, in BRAFV600 colorectal cancer, targeting EGFR—the RTK thought to be the primary driver of feedback reactivation from preclinical studies—in combination with BRAF inhibition, has led to an improvement in clinical efficacy (34–39).”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > DISCUSSION
What the sources say
- Supportedcites [34] Corcoran, 2018, Combined BRAF, EGFR, and MEK inhibition in patients with BRAFV600E-mutant colorectal cancer, Cancer Discov source
The Discussion (page not provided) reports modest clinical activity with BRAF plus EGFR inhibition compared with BRAF inhibitor monotherapy. The Results (page not provided) give a 10% confirmed response rate for that combination, while the Introduction reports 5% for vemurafenib alone. The paper also describes EGFR as a proposed driver of feedback reactivation, while noting that other mechanisms can contribute. (LLM, conf=0.92)
- Supportedcites [35] van Geel, 2017, A phase Ib dose-escalation study of encorafenib and cetuximab with or without alpelisib in metastatic BRAF-mutant colorectal cancer, Cancer Discov source
The Discussion states that BRAF or EGFR inhibitors alone had limited activity in BRAF-mutant metastatic colorectal cancer, whereas clinical studies of combinations showed improved efficacy. The Introduction also describes EGFR-mediated pathway reactivation as a reason for poor response to BRAF inhibition. Page numbers are not supplied in our copy. (LLM, conf=0.93)
- Partly supportedcites [36] Yaeger, 2015, Pilot trial of combined BRAF and EGFR inhibition in BRAF-mutant metastatic colorectal cancer patients, Clin Cancer Res sourceExperimental — accuracy not yet measured
The Discussion reports enhanced activity for combined BRAF and EGFR inhibition compared with historical data for vemurafenib alone. But the study was small and had no vemurafenib-only control arm, so it does not establish the clinical improvement as firmly as the citing sentence implies. (LLM, conf=0.83)
- Not checked — no full text of the sourcecites [37] Kopetz, 2017, Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG S1406), J Clin Oncol source
- Supportedcites [38] Cutsem, 2019, Binimetinib, encorafenib, and cetuximab triplet therapy for patients with BRAF V600E–mutant metastatic colorectal cancer: safety lead-in results from the phase III BEACON Colorectal Cancer Study, J Clin Oncol source
The Introduction (page not provided) states that BRAF inhibition triggers EGFR feedback activation in BRAF V600E–mutant colorectal cancer cells. It also reports that clinical studies confirmed improved activity when EGFR-targeted therapy was added to BRAF inhibition. (LLM, conf=0.94)
- Partly supportedcites [39] Hyman, 2015, Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations, N Engl J Med sourceExperimental — accuracy not yet measured
The Results > Efficacy section reports one response with vemurafenib plus cetuximab in BRAF V600–mutated colorectal cancer, versus none with vemurafenib alone. It does not establish an overall improvement in clinical efficacy: median progression-free and overall survival were shorter in the combination cohort, and the Discussion describes its clinical activity as modest. Page numbers were not available in our copy. (LLM, conf=0.85)
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.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“supporting previous findings that SHP2 perhaps plays a more important role in KRASG12C-driven tumor growth in vivo (27,28).”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > RESULTS > Combined KRASG12C and SHP2 inhibition drives tumor regressions in vivo
What the sources say
- Supportedcites [27] Mainardi, 2018, SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo, Nat Med sourceExperimental — accuracy not yet measured
In the in-vivo tumor-growth results (Fig. 3f; lines 125–131), SHP2 inhibition severely inhibited growth of tumors driven by KRAS G12C. The paper also reports little effect under standard cell-culture conditions (opening summary; lines 38–44), supporting the suggested greater importance in vivo. The result is not unique to G12C: KRAS G12V tumors were also inhibited. (LLM, conf=0.88)
- Partly supportedcites [28] Ruess, 2018, Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase, Nat Med sourceExperimental — accuracy not yet measured
The tumor-maintenance results (lines 140–153) report slower in vivo tumor growth after SHP2 loss in KRASG12D models and in xenografts bearing KRASG12D or KRASG12V. The paper supports a role for SHP2 in mutant-KRAS tumor growth, but the passages do not establish that its role is greater in KRASG12C-driven tumors. (LLM, conf=0.85)
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.
- Supported
- Probably not a substantial claim. 13
- It may state two separate claims as one. 25
- The quote only partly states this claim. 1
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“which is consistent with prior studies suggesting that PI3K is not universally tied to RAS activity (15,29).”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > RESULTS > SHP2 inhibition reduces feedback reactivation in response to KRASG12C inhibitors
What the sources say
- Not checked — no full text of the sourcecites [15] Misale, 2019, KRAS G12C NSCLC models are sensitive to direct targeting of KRAS in combination with PI3K inhibition, Clin Cancer Res source
- Supportedcites [29] Ebi, 2011, Receptor tyrosine kinases exert dominant control over PI3K signaling in human KRAS mutant colorectal cancers, J Clin Invest source
The Results (Figure 2) distinguish the pathways: ERK activation is primarily regulated by mutant KRAS, whereas PI3K/AKT requires RTK-induced activation in the KRAS-mutant colorectal cancers studied. This supports the qualified claim that PI3K is not universally tied to RAS activity. (LLM, conf=0.91)
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.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Indeed, inhibition of SHP2 was recently shown to overcome RTK-driven adaptive feedback mechanisms to MEK inhibition, and enhance the efficacy of MEK inhibitor induced growth suppression in vitro and in vivo in RAS-driven cancers (27,41–44).”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > DISCUSSION
What the sources say
- Supportedcites [27] Mainardi, 2018, SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo, Nat Med source
The main text (lines 46–78; page unavailable) describes RTK-mediated feedback after MEK inhibition and reports that SHP2 inhibition prevented ERK reactivation and enhanced MEK-inhibitor effects in KRAS-mutant cancer cell lines. It also reports that combined SHP2 and MEK inhibition caused regression of a KRAS-mutant lung cancer xenograft, whereas MEK inhibition alone was mainly ineffective (lines 205–214; page unavailable). (LLM, conf=0.93)
- Supportedcites [41] Fedele, 2018, SHP2 inhibition prevents adaptive resistance to MEK inhibitors in multiple cancer models, Cancer Discov source
The Discussion reports that combined MEK/SHP2 inhibition blocks cell proliferation and promotes tumor shrinkage, including in KRAS-mutant cancers. The Results report that SHP099 blocks MEK-inhibitor-induced ERK reactivation and document RTK-driven adaptive resistance in vivo. The supplied passages do not provide page numbers. (LLM, conf=0.93)
- Partly supportedcites [42] Ahmed, 2019, SHP2 drives adaptive resistance to ERK signaling inhibition in molecularly defined subsets of ERK-dependent tumors, Cell Rep sourceExperimental — accuracy not yet measured
The Results section reports that combined MEK and SHP2 inhibition suppressed ERK signaling and cell growth in RAS(G12X)-mutant tumor cell lines. It also reports reduced tumor growth in vivo, but that experiment used BRAF(V600E) RKO xenografts and combined RAF, MEK, and SHP2 inhibitors. Thus, this paper does not establish the claimed in vivo enhancement of MEK-inhibitor growth suppression in RAS-driven cancers. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [43] Lu, 2019, SHP2 inhibition overcomes RTK-mediated pathway re-activation in KRAS mutant tumors treated with MEK inhibitors, Mol Cancer Ther source
- Partly supportedcites [44] Wong, 2018, Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition, Nat Med sourceExperimental — accuracy not yet measured
In the copy’s section labeled Abstract (page not provided), SHP2 inhibition blocked adaptive signaling and enhanced MEK-inhibitor growth suppression in vitro and in vivo in KRAS-amplified gastric cancer models. The claim’s broader reference to RAS-driven cancers is not supported by these results: adding SHP2 inhibition did not improve tumor-growth suppression in the KRAS-mutant xenograft model. (LLM, conf=0.88)
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.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“For instance, BRAF inhibitors led to a monotherapy response rate of >50% in BRAFV600E melanoma and ~30% in BRAFV600E NSCLC, but only ~5% in BRAFV600E colorectal cancer, likely due to the variable robustness of adaptive feedback networks in each tumor type (45–49).”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > DISCUSSION
What the sources say
- Partly supportedcites [45] Sosman, 2012, Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib, N Engl J Med sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
- Partly supportedcites [46] Planchard, 2016, Dabrafenib in patients with BRAF(V600E)-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial, Lancet Oncol sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
- Partly supportedcites [47] Kopetz, 2015, Phase II pilot study of vemurafenib in patients with metastatic BRAF-mutated colorectal cancer, J Clin Oncol sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Partly supportedcites [48] Karoulia, 2017, New perspectives for targeting RAF kinase in human cancer, Nat Rev Cancer sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Partly supportedcites [49] Flaherty, 2012, Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations, N Engl J Med sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
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.
- 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
“the pan-HER inhibitor afatinib and the FGFR inhibitor BGJ398 displayed the greatest and most consistent cooperativity with ARS-1620, though neither combination was universally effective in all models.”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > RESULTS > Adaptive resistance to KRASG12C inhibition is driven by multiple RTKs
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.
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 observed a strong induction of both NRAS-GTP and HRAS-GTP levels and rebound in downstream MAPK signaling (phospho-ERK, phospho-RSK) upon treatment with AMG 510”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > RESULTS > Feedback reactivation of RAS signaling following KRASG12C inhibition
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.
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
“KRASG12C cell lines demonstrated a heterogeneous response to RTK inhibition, with select inhibitors enhancing anti-tumor effect in combination, relative to ARS-1620 alone.”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > RESULTS > Adaptive resistance to KRASG12C inhibition is driven by multiple RTKs
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
“In all cell lines, ARS-1620 suppressed MAPK pathway signaling, a key downstream effector pathway of KRAS, as measured by inhibition of phospho-MEK, phospho-ERK, and phospho-RSK at 4 hours”
- Also stated in: § Feedback reactivation of RAS signaling following KRASG12C inhibition · plain
“However, by 24–48 hours, RAS-MAPK pathway signaling began to rebound from the nadir of pathway suppression, leading to pathway reactivation and incomplete suppression by 72 hours”
- Also stated in: § Feedback reactivation of RAS signaling following KRASG12C inhibition · plain
“A similar rebound in RAS-MAPK signaling was also observed with the more recently available clinical KRASG12C inhibitor AMG 510”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > RESULTS > Feedback reactivation of RAS signaling following KRASG12C inhibition
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. The quote only partly states this claim.
- Also stated in: § Feedback reactivation of RAS signaling following KRASG12C inhibition · plain
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
“following 48 hours of treatment with ARS-1620, we observed an adaptive increase in the phosphorylation levels of multiple RTKs, including EGFR, HER2, FGFR, and c-MET, but with a highly heterogeneous pattern across cell line models”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > RESULTS > Adaptive resistance to KRASG12C inhibition is driven by multiple RTKs
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
“SW1463 showed primary dependence on EGFR/HER family signaling (erlotinib, afatinib), as compared to FGFR signaling (BGJ398), whereas MIA Paca-2 appeared to be more dependent on FGFR signaling and showed less dependence on EGFR/HER family signaling.”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > RESULTS > Adaptive resistance to KRASG12C inhibition is driven by multiple RTKs
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
“combined KRASG12C/SHP2 inhibition drove sustained RAS pathway suppression and improved efficacy in vitro and in vivo.”
- Also stated in: § INTRODUCTION · plain
“the combination of KRASG12C and SHP2 inhibitors leads to sustained RAS pathway suppression and improved efficacy in vitro and in vivo.”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > Abstract > Results:
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.
- Rests on an assumption: The KRASG12C-mutant cell lines and xenograft models used are representative of KRASG12C-mutant human cancers, so findings generalize to patients.
- Rests on an assumption: Effects on cell viability in vitro and xenograft tumor growth in vivo predict clinical efficacy of KRASG12C inhibitor combinations.
- Also stated in: § INTRODUCTION · plain
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
“with the afatinib combination appearing to produce the greatest effect in SW837 xenografts (though not significant, p=0.37 vs ARS-1620 alone)”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > RESULTS > Adaptive resistance to KRASG12C inhibition is driven by multiple RTKs
hedged- 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
“in contrast with MIA PaCa-2 xenografts, in which the BGJ398 combination appeared to produce the greatest effect (though not significant, p=0.13 vs ARS-1620 alone)”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > RESULTS > Adaptive resistance to KRASG12C inhibition is driven by multiple RTKs
hedged- 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
“A similar pattern of more complete suppression of the MAPK pathway was also observed with ARS-1620 combined with the SHP2 inhibitor RMC-4550 (Supplementary Fig. S5) and AMG 510 combined with either SHP099 or RMC-4550 (Supplementary Fig. S1).”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > RESULTS > SHP2 inhibition reduces feedback reactivation in response to KRASG12C inhibitors
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.
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
“Combined KRASG12C and SHP2 inhibition more effectively suppressed tumor cell viability at 72 hours, leading to GI50 shifts of ~5 to 30-fold in six of eight KRASG12C models (Supplementary Fig. S7).”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > RESULTS > SHP2 inhibition reduces feedback reactivation in response to KRASG12C inhibitors
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
“Combined inhibition of KRASG12C and SHP2 with ARS-1620 and SHP099 also led to more complete suppression of the MAPK pathway over time in all models, exhibiting a strong reduction in feedback reactivation of the pathway (Fig. 3B–C; Supplementary Fig. S6).”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > RESULTS > SHP2 inhibition reduces feedback reactivation in response to KRASG12C inhibitors
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.
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
“However, for each of these inhibitors, there are models in which pathway feedback reactivation appears independent of each specific RTK—i.e. MIA PaCa2 for afatinib, and SW1463 for BGJ398 (Fig. 2A)”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > DISCUSSION
hedged- 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
“combined KRASG12C and SHP2 inhibition suppressed pathway signaling and enhanced efficacy in all models”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > 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.
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 rebound reactivation was observed even at the highest concentrations of ARS-1620, suggesting that pathway rebound is not due simply to inadequate levels of inhibitor.”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > RESULTS > Feedback reactivation of RAS signaling following KRASG12C inhibition
hedged- 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
“the variable induction of multiple RTKs across different KRASG12C models following ARS-1620 treatment and different levels of phospho-RTKs at baseline suggests that distinct and/or multiple RTKs may drive adaptive feedback across different KRASG12C cancers, and that strategies targeting a single RTK may not be universally effective.”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > RESULTS > Adaptive resistance to KRASG12C inhibition is driven by multiple RTKs
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.
- Rests on an assumption: The KRASG12C-mutant cell lines and xenograft models used are representative of KRASG12C-mutant human cancers, so findings generalize to patients.
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 support that combined KRASG12C and SHP2 inhibition may overcome adaptive feedback resistance and may represent a promising therapeutic strategy for future clinical trials in KRASG12C mutant cancers.”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > RESULTS > Combined KRASG12C and SHP2 inhibition drives tumor regressions in vivo
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.
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
“Cell lines were obtained from ATCC or the Center for Molecular Therapeutics at the MGH Cancer Center (Boston, MA), which routinely performs cell line authentication testing by SNP and short tandem repeat analysis, and maintained in DMEM/F12 supplemented with 10% fetal calf serum, and were not cultured longer than 6 months after receipt from cell banks.”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > MATERIALS AND METHODS > Cell lines and inhibitors
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
“suggesting that pan-HER or FGFR co-targeting could be promising strategies.”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > DISCUSSION
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.
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
“Targeting a dominant RTK driving adaptive feedback reactivation is an attractive strategy to suppress adaptive resistance, as it intercepts the critical feedback loop at its most upstream point.”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > 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.
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
“and that strategies to overcome this mechanism may be key to improving clinical efficacy.”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > DISCUSSION
hedgedconditional- 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.
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
“However, additional combinations exploring potential synthetic lethal interactions with other pathways may also be key to maximizing efficacy.”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check 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. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.
In the paper
“However, not all patients respond to therapy, and the durability of benefit may be limited”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [16] Govindan, 2019, 446PDPhase I study of AMG 510, a novel molecule targeting KRAS G12C mutant solid tumours, Ann Oncol source
hedged- 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
“and a study by Molina-Arcas et al suggested targeting IGFR and mTOR (15,52).”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [15] Misale, 2019, KRAS G12C NSCLC models are sensitive to direct targeting of KRAS in combination with PI3K inhibition, Clin Cancer Res source
- Not matchedcites [52]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedconditional- 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
“For example, a study by Misale et al, suggested that targeting the PI3K/AKT pathway, which is often activated independently of RAS, may improve the efficacy of KRASG12C inhibitors”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [15] Misale, 2019, KRAS G12C NSCLC models are sensitive to direct targeting of KRAS in combination with PI3K inhibition, Clin Cancer Res source
hedgedconditional- 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
“The initial reports of single-agent activity of KRASG12C inhibitors in patients with KRASG12C cancers are promising and support that mutant RAS represents a valid clinical target.”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [16] Govindan, 2019, 446PDPhase I study of AMG 510, a novel molecule targeting KRAS G12C mutant solid tumours, Ann Oncol source
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.
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 data support SHP2 as a promising combination partner for KRASG12C inhibitors, capable of abrogating adaptive feedback reactivation from multiple RTKs to maintain RAS pathway suppression and enhance efficacy in vitro and in vivo.”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > 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.
In the paper
“In 55 patients with KRASG12C cancers treated with the KRASG12C inhibitor AMG-510, a 24% overall response rate was reported, with 11 responses observed in 23 non-small cell lung cancer (NSCLC) patients, but only 1 response seen in 26 colorectal cancer patients(16).”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [16] Govindan, 2019, 446PDPhase I study of AMG 510, a novel molecule targeting KRAS G12C mutant solid tumours, Ann Oncol source
plainn = 55- 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
“and determining the most effective clinical strategy may be a critical first step.”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > DISCUSSION
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check 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. It may be too vague to check against evidence. 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
“these data suggest that SHP2 inhibitors, either alone or perhaps in combination with specific RTK inhibitors or downstream inhibitors of the RAS-MAPK pathway, could be promising therapeutic strategies for future clinical trials.”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > DISCUSSION
hedgedconditional- 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.
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
“and that vertical inhibition of the RAS pathway, such as combined SHP2 and KRASG12C inhibition, may represent a promising strategy for evaluation in future clinical trials.”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > DISCUSSION
hedgedconditional- 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.
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
“Initially, combinations may need to focus on improving suppression of RAS signaling by combining KRASG12C inhibitors with agents targeting adaptive feedback—such as RTK inhibitors, SHP2 inhibitors, or perhaps downstream pathway inhibitors (i.e. MEK or ERK)”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > DISCUSSION
hedgedconditional- 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.
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
“suggesting that strategies to target key resistance mechanisms may improve clinical efficacy.”
§ Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition > DISCUSSION
hedgedconditional- 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.
The paper relies on this without support.
The KRASG12C-mutant cell lines and xenograft models used are representative of KRASG12C-mutant human cancers, so findings generalize to patients.
“we evaluated the effects of the KRASG12C inhibitor ARS-1620 across a panel of eight KRASG12C-mutant cell lines”
“SW837 and MIA PaCa-2 cell lines (5×106) were injected into 6–8 week old female athymic nude mice”
The paper relies on this without support.
Effects on cell viability in vitro and xenograft tumor growth in vivo predict clinical efficacy of KRASG12C inhibitor combinations.
“combined KRASG12C/SHP2 inhibition drove sustained RAS pathway suppression and improved efficacy in vitro and in vivo”
“highlight the potential importance of vertical inhibition strategies to enhance the clinical efficacy of KRASG12C inhibitors”
The paper relies on this without support.
KRASG12C cycles between a GDP-bound inactive state and a GTP-bound active state.
“Because KRASG12C actively cycles between its GDP-bound inactive state and its GTP-bound active state”
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 cited source doesn’t support the claim as written.
In the citing paper
“These combinations, however, are mostly cytostatic, limiting the potential for clinical benefit.”
From BCL-XL PROTAC degrader DT2216 synergizes with sotorasib in preclinical models of KRASG12C-mutated cancers (2022) · cites this paper as [3]
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Despite the clinical benefit that was observed for many patients treated with KRASG12C inhibitors, acquired resistance to single-agent therapy eventually occurred in most patients.”
From Acquired Resistance to KRAS G12C Inhibition in Cancer (2021) · cites this paper as [15]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“the combination of ARS1620 with an anaplastic lymphoma kinase (ALK) inhibitor or FGFR inhibitor has shown effectiveness in H358 and H23 cell lines, but its efficacy is substantially diminished in H1792, SW1463, and SW1573 cell lines (12).”
From YAP/TAZ mediates resistance to KRAS inhibitors through inhibiting proapoptosis and activating the SLC7A5/mTOR axis (2024) · cites this paper as [12]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Previous studies have shown that vertical inhibition of EGFR and SHP-2 (upstream RAS molecules), suppresses feedback reactivation and has stronger antitumor effects than monotherapy (8,27).”
From Cetuximab Enhances the Efficacy of MRTX1133, a Novel KRASG12DInhibitor, in Colorectal Cancer Treatment (2023) · cites this paper as [27]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“For example, KRAS G12C inhibition produces substantially different outcomes in NSCLC and CRC, largely due to lineage-specific feedback regulation [23,26,27,28,32].”
From Precision Targeting of KRAS-Mutant Cancers: Beyond G12C Toward G12D and Pan-RAS Therapeutic Strategies (2026) · cites this paper as [26]
Experimental — accuracy not yet measured
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
“This discrepancy could not be solely attributed to diverse experimental systems adopted between research groups since both of them used cell lines, such as H358, H23, and H1792 in ARS-1620 study, and GTP-bound K-Ras was further analyzed using similar assays.10,11”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [11]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Although long-term efficacy of K-RasG12C-targeted therapies in patients is still unknown,6,50 adaptive resistance to both AMG-510 and MRTX849 has been observed in preclinical animal models.7,11”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [11]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Given the individual-specific involvement of RTK, targeting common nodes downstream of multiple RTK signaling pathways may represent a feasible strategy to overcome adaptive Ras reactivation across heterogeneous KRAS mutant cancers.11,84”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [11]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Since acquired resistance primarily occurs via adaptive RTK-SHP2-induced reactivation of Ras and its downstream effectors,10,11 combining K-RasG12C inhibitor with drugs targeting RTK signaling might be beneficial.”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [11]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In several intrinsically resistant cell lines, the MAPK and PI3K/mTOR pathways were reactivated within 24–48 hours of treatment with KRAS G12C inhibitors, despite continued suppression of GTP-bound KRAS (11, 12).”
From YAP/TAZ mediates resistance to KRAS inhibitors through inhibiting proapoptosis and activating the SLC7A5/mTOR axis (2024) · cites this paper as [12]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Combination strategies targeting KRAS G12C and upstream regulators or downstream effectors of the RAS signaling have been extensively explored to overcome resistance to sotorasib or adagrasib (9–12, 56).”
From YAP/TAZ mediates resistance to KRAS inhibitors through inhibiting proapoptosis and activating the SLC7A5/mTOR axis (2024) · cites this paper as [12]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Additionally, bypass signaling pathways like the MAPK or PI3K pathway can become activated without involving mutational events (10, 12).”
From YAP/TAZ mediates resistance to KRAS inhibitors through inhibiting proapoptosis and activating the SLC7A5/mTOR axis (2024) · cites this paper as [12]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“We and others have recently described mechanisms of acquired resistance in patients with lung and colorectal cancer (CRC) treated with KRASG12C inhibitors, including mutations in KRAS or other RTK–RAS–MAPK pathway effectors, adaptive signaling alterations, and histologic transformation to drug-resistant cell states (14, 18–24).”
From Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer (2024) · cites this paper as [21]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Recent studies using preclinical models have indicated that acquired resistance to KRASG12C inhibition may be mediated by the activation of multiple receptor tyrosine kinase (RTK) regulators, including epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), insulin-like growth factor 1 receptor (IGF1R), human epidermal growth factor 2 (HER2), and Src homology 2 domain-”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [6]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“One major route leading to such recovery of RAS activity is the activation of RTKs through either genetic (e.g., gene amplification or fusion) or non-genetic mechanisms.2,4,5,6,7,8,22,23,24,25”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [6]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Despite the encouraging antitumor activity with single-agent divarasib in patients with CRC, adaptive feedback reactivation of RAS–MAPK signaling, a proposed key mechanism of resistance to KRAS G12C inhibition in CRC, occurs frequently and ultimately limits efficacy12–14.”
From Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial (2024) · cites this paper as [14]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Rapid reactivation of RAS signaling, mediated by EGFR, FGFR, HER2, and c-MET, was detected in multiple KRAS G12C CRC, PDAC, and NSCLC cell lines treated with ARS-1620 and sotorasib [71].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [71]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“However, clinical efficacy remains limited by intrinsic and acquired resistance, adaptive pathway reactivation, and tumor heterogeneity.”
From Precision Targeting of KRAS-Mutant Cancers: Beyond G12C Toward G12D and Pan-RAS Therapeutic Strategies (2026) · cites this paper as [26]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“KRAS-mutant CRC frequently exhibits strong dependency on EGFR-mediated feedback signaling, particularly after KRAS G12C inhibition [26,27,28,32,33,56].”
From Precision Targeting of KRAS-Mutant Cancers: Beyond G12C Toward G12D and Pan-RAS Therapeutic Strategies (2026) · cites this paper as [26]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“several studies have shown that similar pathway reactivation occurs upon KRASG12C-inhibitor treatment50,110–113.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [112]
The cited source says what the claim attributes to it.
In the citing paper
“the inhibition of SHP2, which connects RTKs to the RAS signaling pathway and is particularly vulnerable in cancer cells with genetic alteration in KRAS, has attracted considerable attention (12, 56–59).”
From YAP/TAZ mediates resistance to KRAS inhibitors through inhibiting proapoptosis and activating the SLC7A5/mTOR axis (2024) · cites this paper as [12]
The cited source says what the claim attributes to it.
In the citing paper
“To enhance its efficacy, sotorasib has been evaluated in preclinical studies using different combinations [2–4].”
From BCL-XL PROTAC degrader DT2216 synergizes with sotorasib in preclinical models of KRASG12C-mutated cancers (2022) · cites this paper as [3]
The cited source says what the claim attributes to it.
In the citing paper
“Our study similarly revealed the activation of multiple RTKs in AMG510-R tumors upon characterization of AMG510-R tumors from mouse iKras-escaper mice and CRC PDX models, consistent with a recent study using human cancer cell lines.6”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [6]
The cited source says what the claim attributes to it.
In the citing paper
“Despite the encouraging antitumor activity with single-agent divarasib in patients with CRC, adaptive feedback reactivation of RAS–MAPK signaling, a proposed key mechanism of resistance to KRAS G12C inhibition in CRC, occurs frequently and ultimately limits efficacy12–14.”
From Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial (2024) · cites this paper as [14]
The cited source says what the claim attributes to it.
In the citing paper
“It is therefore not surprising that RTKs function as crucial mediators of response to KRAS-targeted therapy [71].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [71]
The cited source says what the claim attributes to it.
In the citing paper
“Combined inhibition of KRAS G12C with SHP2, a phosphatase that serves as a common mediator of RTK signaling to RAS(31), has been proposed as another combination to overcome the feedback reactivation in KRAS G12C tumors(32).”
From EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer. (2020) · cites this paper as [32]
The cited source says what the claim attributes to it.
In the citing paper
“Pharmacologic inhibition of SHP2 suppresses RTK-mediated RAS activation and has demonstrated preclinical activity in KRAS-driven cancers [16,26].”
From Precision Targeting of KRAS-Mutant Cancers: Beyond G12C Toward G12D and Pan-RAS Therapeutic Strategies (2026) · cites this paper as [26]
The cited source says what the claim attributes to it.
In the citing paper
“Pharmacologic inhibition of SHP2 suppresses RTK-mediated RAS activation and has demonstrated preclinical activity in KRAS-driven cancers [16,26].”
From Precision Targeting of KRAS-Mutant Cancers: Beyond G12C Toward G12D and Pan-RAS Therapeutic Strategies (2026) · cites this paper as [26]
The cited source says what the claim attributes to it.
In the citing paper
“Previous studies evidenced that RTK/kinase feedback activation is among the main mechanisms of adaptive resistance to KRASG12C inhibitors”
From Bcl-xL Is a Key Mediator of Apoptosis Following KRASG12C Inhibition in KRASG12C -mutant Colorectal Cancer (2023) · cites this paper as [42]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“The mechanisms of acquired resistance to these therapies are currently unknown.”
From Acquired Resistance to KRAS G12C Inhibition in Cancer (2021) · cites this paper as [15]
Experimental — accuracy not yet measuredIn the citing paper
“Notably, multiple RTKs are attributed to this process, implying that attenuation of this adaptive resistance by targeting a single RTK may not be an effective strategy [8].”
From Genome-wide CRISPR-cas9 knockout screening identifies GRB7 as a driver for MEK inhibitor resistance in KRAS mutant colon cancer (2022) · cites this paper as [8]
In the citing paper
“Although two small molecules, AMG510 and MRTX849, which target KRAS G12C have entered clinical trials, these inhibitors produced less profound activity in CRC than non-small cell lung cancer patients [6–10].”
From Genome-wide CRISPR-cas9 knockout screening identifies GRB7 as a driver for MEK inhibitor resistance in KRAS mutant colon cancer (2022) · cites this paper as [8]
In the citing paper
“Previous studies demonstrating an elevated pool of GDP-bound KRASG12C under SHP2 inhibition (38, 48) provide a rationale for combining JDQ443 and the SHP2 inhibitor TNO155.”
In the citing paper
“Another major determinant of KRASG12C inhibitor resistance is the reactivation of upstream tyrosine kinase signaling that promotes SOS1-dependent GTP loading on RAS family members (19, 38, 44, 48–50).”
In the citing paper
“However, therapeutic resistance to K-RasG12C inhibition is not only noted in preclinical tumor models,10, 11, 12 but also in the clinic.”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [11]
In the citing paper
“They found that Ras downstream effectors, including MEK, ERK, and 40S ribosomal protein S6 kinase were reactivated 24–48 h after ARS-1620 and AMG-510 treatment, despite a rapid inactivation of these molecules within 4 h.11”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [11]
In the citing paper
“However, in direct contrast to findings made by Xue et al.,10 increased GTP-bound wild-type Ras (N-Ras and H-Ras) proteins were responsible for restoring MAPK activation after drug treatments, whereas K-Ras is maintained in its inactive state.11”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [11]
In the citing paper
“although individual genetic alterations, including TP53 (tumor protein p53), CDKN2A (cyclin-dependent kinase inhibitor 2A), STK11 (serine/threonine kinase 11), and KRAS mutant allele frequency failed to predict adaptive resistance.6,7,11”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [11]
In the citing paper
“Although how SHP2 activates Ras is still an open question, studies made by Ryan et al.,11 Xue et al.,10 and their colleagues showed that concurrent inhibition of SHP2 and K-RasG12C by small-molecule inhibitors (e.g., SHP099 and ARS-1620) enhanced the antiproliferative effects of KRASG12C inhibitors in both in vitro and in vivo models.”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [11]
In the citing paper
“Their results indicated that after ARS-1620 treatment, the phosphorylation of multiple RTKs increased with high heterogeneity among different KRASG12C mutant models.”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [11]
In the citing paper
“Adaptive Ras reactivation through RTK-SHP2 pathway is one of the well-characterized mechanisms accountable for acquired resistance to K-RasG12C inhibition.10,11”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [11]
In the citing paper
“Ryan et al.112 described adaptive resistance to sotorasib and ARS-1620 resulting from activation of wild-type NRAS and HRAS in KRASG12C-mutant lung, colon and pancreatic cancer cell lines.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [112]
In the citing paper
“Accordingly, KRASG12Ci plus SHP2 inhibitor (SHP2i; for example TNO155) or EGFR antagonist (EGFRi; for example cetuximab18) combination approaches are now being clinically tested13,16,19,20, with evidence of improved clinical response20–22.”
From Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance (2024) · cites this paper as [16]
In the citing paper
“Combination approaches that co-target regulators upstream of KRAS, including receptor tyrosine kinases (RTKs) and SHP2, improve KRASG12Ci response in preclinical models13,15–17.”
From Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance (2024) · cites this paper as [16]
In the citing paper
“Mechanistically, this approach may block pathway feedback activation and shift both mutant and WT RAS to the GDP-bound state, thus enhancing downregulation of RAS-MAPK pathway signaling by KRASG12Ci (refs. 13,16).”
From Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance (2024) · cites this paper as [16]
In the citing paper
“Although combination approaches induced enhanced antiproliferative effects, a moderate rebound of MAPK pathway activity, which might be associated with adaptive resistance to KRASG12C targeted therapy13,16, was observed in all models by 48 h after treatment.”
From Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance (2024) · cites this paper as [16]
In the citing paper
“Here, we show that co-administration of BI-3406 with adagrasib in preclinical KRASG12C-mutant NSCLC and CRC models enhances the magnitude and duration of the antitumor response, and is comparable to those induced by clinically evaluated combinations, such as KRASG12Ci plus SHP2i or EGFRi (refs. 16,20,21).”
From Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance (2024) · cites this paper as [16]
In the citing paper
“In the remaining patients, no genomic mechanisms of resistance could be identified13,16,17,47, suggesting that non-genetic alterations could be involved.”
From Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance (2024) · cites this paper as [16]
In the citing paper
“The described benefit of SHP2 and KRAS G12C inhibition supports further investigation of combination therapy approach to prevent upregulation of upstream pathways24.”
From Selective KRAS G12C inhibitors in non-small cell lung cancer: chemistry, concurrent pathway alterations, and clinical outcomes (2021) · cites this paper as [24]
In the citing paper
“We and others reported previously that SHP2 inhibition enhances G12Ci action in vitro and in mice (16,45,46)”
From Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRASG12C Inhibitor Efficacy (2023) · cites this paper as [45]
In the citing paper
“However, the initial enthusiasm has been somewhat tempered by work suggesting that acquired resistance may constrain the inhibitors’ efficacy, which indicates that combination therapies may be needed11–14.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [14]
In the citing paper
“These studies reported that adaptive response to G12C-Is could be minimized by combining G12C-I with RTK or SHP2-Is (Hallin et al., 2020; Lou et al., 2019; Ryan et al., 2020; Xue et al., 2020).”
From SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling (2021) · cites this paper as Ryan et al., 2020
In the citing paper
“Target combinations that can abrogate this adaptive resistance mechanism, including vertical drug combination within the MAPK pathway (43) and co-inhibition of parallel RTK/PI3K signaling (40, 44, 45), could result in a more sustained inhibition of cell viability in KRAS mutant cells.”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [43]
In the citing paper
“Like Ryan et al. (2020), we observed induction of RTKs/RTK ligand genes following ARS treatment”
From SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling (2021) · cites this paper as Ryan et al., 2020
In the citing paper
“Ryan et al. observed rapid adaptive RAS pathway feedback reactivation following treatment by KRAS G12C inhibitors ARS-1620 and AMG 510 [97]. This RAS pathway feedback reactivation was observed in the majority of KRAS G12C models and was driven by RTK-mediated activation of wild-type RAS isoforms and was refractory to inhibition by G12C-specific inhibitors.”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [97]
In the citing paper
“RNA sequencing revealed that KRAS (G12C) inhibition causes significant repression of DUSP, SPRY, and PHLDA family genes known as negative regulators of MAPK pathway [115, 116].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [116]
In the citing paper
“KRAS G12C inhibition alone by either AMG510 or MRTX849 resulted in decreased activities for PI3K/AKT, MAPK, and mTOR signaling pathways to differing degrees for various KRAS G12C mutant cell lines (Figure 1E–Q).”
From Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK–YAP Signaling (2021) · cites this paper as [20]
In the citing paper
“Recent studies have shown that strategies to combine the inhibitors targeting either KRAS upstream or downstream signaling components with KRAS G12C inhibitors can prolong the antitumor effects of treatments, indicating that the vertical signaling of KRAS is important to maintain the drug effects.[ 8, 9, 20 ]”
From Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK–YAP Signaling (2021) · cites this paper as [20]
Citations
Cites
COSMIC: the Catalogue Of Somatic Mutations In Cancer
Tate, J. G., Bamford, S., Jubb, H. C., Sondka, Z., Beare, D. M., Bindal, N., Boutselakis, H., Cole, C. G., Creatore, C., Dawson, E., et al. (2019) · Nucleic Acids Research · doi:10.1093/nar/gky1015 · Cited by 4,867 · cited 1×
“The KRAS 102 mutation represents 11% of all KRAS mutations (COSMIC v89)(1,8), but is the most 103 common RAS mutation in lung cancer and also occurs in many other types of cancer, 104 such as colon and pancreatic cancers.”
BackgroundCombined BRAF and MEK inhibition in melanoma with BRAF V600 mutations
Flaherty, K. T., Infante, J. R., Daud, A., Gonzalez, R., Kefford, R. F., Sosman, J., Hamid, O., Schuchter, L., Cebon, J., Ibrahim, N., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1210093 · Cited by 2,810
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Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR
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“For example, RTK-driven feedback reactivation of RAS-MAPK signaling has been identified as a key driver of resistance in BRAF cancers treated with BRAF inhibitors (colorectal cancer in particular) and in KRAS-mutant cancers treated with MEK inhibitors (11, 12, 32).”
BackgroundVemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations
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Multiple Ras-dependent phosphorylation pathways regulate Myc protein stabilityPreprint
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Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor
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“For example, RTK-driven feedback reactivation of RAS-MAPK signaling has been identified as a key driver of resistance in BRAF cancers treated with BRAF inhibitors (colorectal cancer in particular) and in KRAS-mutant cancers treated with MEK inhibitors (11, 12, 32).”
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Cited by
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The current state of the art and future trends in RAS-targeted cancer therapies
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“Although preclinical studies have nominated putative mechanisms of up-front resistance, including RAS–MAPK pathway reactivation (4, 8), mechanisms of acquired resistance to MRTX849 or AMG 510 causing disease relapse in patients remain unknown.”
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Metadata
- Authors
- Ryan, M. B., Fece de la Cruz, F., Phat, S., Myers, D. T., Wong, E., Shahzade, H. A., Hong, C. B., & Corcoran, R. B.
- Affiliations
- Harvard University (US)
- 1Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
- Corresponding author
- Corcoran, Ryan B.
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2020-04-01
- Volume
- 26
- Issue
- 7
- Pages
- 1633-1643
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC7124991
- OpenAlex
- W2990053855
- Cited by
- 496
- References
- 54
- Citations by year
- 2026: 77 · 2025: 78 · 2024: 88 · 2023: 73 · 2022: 73 · 2021: 77 · 2020: 29
- FWCI
- 14.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- NIH NCI (P50 CA127003,, R01CA208437, U54CA224068)
- Stand Up To Cancer (SU2C-AACR-DT22-17)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- KRAS G12C, KRAS inhibitors, sotorasib, adaptive resistance, receptor tyrosine kinase signaling, SHP2 inhibition, MEK/ERK inhibitor, combination therapy, Ras isoforms
- MeSH terms
- Feedback, Humans, Mutation, Oncogenes, Piperazines, Pyridines, Pyrimidines, Proto-Oncogene Proteins p21(ras), Protein Kinase Inhibitors
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