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Cited by 231Protein Kinase Regulation and GTPase SignalingMelanoma and MAPK PathwaysProtein Tyrosine Phosphatases

Targeting KRAS mutant cancers: from druggable therapy to drug resistance

Open access
Zhu, Chunxiao, Guan, Xiaoqing, Zhang, Xinuo, Luan, Xin, Song, Zhengbo, Cheng, Xiangdong, Zhang, Weidong, Qin, Jiang-Jiang·2022·Molecular Cancer
DOI 10.1186/s12943-022-01629-2PMC PMC9351107
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Abstract

Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) is the most frequently mutated oncogene, occurring in a variety of tumor types. Targeting KRAS mutations with drugs is challenging because KRAS is considered undruggable due to the lack of classic drug binding sites. Over the past 40 years, great efforts have been made to explore routes for indirect targeting of KRAS mutant cancers, including KRAS expression, processing, upstream regulators, or downstream effectors. With the advent of KRAS (G12C) inhibitors, KRAS mutations are now druggable. Despite such inhibitors showing remarkable clinical responses, resistance to monotherapy of KRAS inhibitors is eventually developed. Significant progress has been made in understanding the mechanisms of drug resistance to KRAS-mutant inhibitors. Here we review the most recent advances in therapeutic approaches and resistance mechanisms targeting KRAS mutations and discuss opportunities for combination therapy.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes therapeutic strategies for KRAS-mutant cancers, from direct KRAS(G12C)/KRAS(G12D) inhibitors to upstream/downstream pathway inhibitors, degradation agents, vaccines, and siRNA. It concludes that resistance to KRAS inhibitors is diverse and tissue-specific, and that combination therapy is promising but limited by toxicity, safety, and cost.

Key findings

KRAS mutations are common in CRC (45% US, 49% China), PDAC (~90% US, ~89% China), and LUAD (35% US, ~13% China); KRAS(G12C) accounts for 41% of LUAD, while G12D and G12V are most common in CRC and PDAC. — Direct inhibitors include FDA-approved AMG510 (sotorasib) for KRAS(G12C), MRTX849 (adagrasib), and the non-covalent KRAS(G12D) inhibitor MRTX1133; MRTX849 caused significant tumor regression in 65% of KRAS(G12C)-positive models. — Resistance mechanisms include secondary KRAS mutations (e.g., R68S, Y96C, H95D/Q/R, Y96D), KRAS amplification, feedback reactivation of EGFR/MAPK/PI3K, EMT, FAK-YAP activation, cell-cycle dysregulation, and immune/TME changes. — Tissue context affects response: in an AMG510 phase I trial, 7/13 NSCLC patients had partial response and 6 had stable disease, whereas only 1/12 CRC patients had partial response and 10 had stable disease.

Methods

Narrative review of recent advances in KRAS-mutant cancer therapeutics and resistance mechanisms, synthesizing preclinical and clinical literature. — Includes summary tables of KRAS-targeted agents (Table 1) and clinical trials (Table 2), plus schematic figures of KRAS signaling, inhibitor binding, and resistance pathways. — No primary experimental data, systematic search strategy, or meta-analysis is reported.

Limitations

Stated: combination therapy is “always been more toxic, with poor safety” and brings greater financial burden; more studies are needed to determine the most effective combination strategy. — Stated: PROTAC safety evaluation, pharmacodynamic studies, and dose selection need improvement, and RNAi-based drugs face delivery and prolonged-activity limitations at tolerated doses. — Evident: as a narrative review, it lacks a formal systematic search/inclusion process and relies on cited studies rather than new patient-level or experimental data.

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Integrity signals

Registry

Crossref · 10.1186/s12943-022-01629-2

Cites

Statistics

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Claims the paper makes

0 of 204 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    GTP binding to KRAS shifts the active site from an open to a closed conformation, allowing multiple downstream effector pathways including MAPK and PI3K to interact and activate.

    “GTP binding to KRAS shifts the active site from an open to a closed conformation, allowing multiple downstream effector pathways to interact and activate, including the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways [12, 13].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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      Not checked in the free run.

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  • Interpretationreasoning

    KRAS activity can be indirectly reduced by inhibiting the function of factors or enzyme activity, achieving inhibition of pathway activation.

    “The KRAS activity can be indirectly reduced by inhibiting the function of factors or enzyme activity, which achieves the purpose of inhibiting pathway activation.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    SOS1 and SHP2 are the two most critical targets in the RAS signaling pathway.

    “Son of sevenless 1 (SOS1) and SH2-containing protein tyrosine phosphatase (SHP2) are the two most critical targets in the RAS signaling pathway [61, 62].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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      Not checked in the free run.

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  • Premisecitation

    AMG510 enhances its binding to KRAS G12C through the His95 groove with an approximately 10-fold increase in potency compared to ARS-1620.

    “In contrast to the ARS-1620, the first confirmed direct inhibitor of KRAS (G12C), which occupies a smaller pouch and is less potent, AMG510 enhances its binding to KRAS (G12C) through the His95 groove with an approximately 10-fold increase in potency [42] (Table 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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      Not checked in the free run.

  • Premisecitation

    The activated state of KRAS accumulating in vivo results in activation of downstream signaling pathways.

    “The activated state of KRAS accumulating in vivo results in the activation of downstream signaling pathways and is associated with tumorigenesis, aggressive disease, and poor prognosis [14, 15].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14] Pells S, Divjak M, Romanowski P, Impey H, Hawkins NJ, Clarke AR, et al. Developmentally-regulated expression of murine K-ras isoforms. Oncogene. 1997;15(15):1781–6. source

      Not checked in the free run.

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    Premisecitation

    Cysmethynil, a small molecule inhibitor of ICMT, disrupts RAS membrane binding and reduces cell growth in RAS mutant cell lines.

    “Cysmethynil, a small molecule inhibitor of ICMT, disrupts RAS membrane binding and reduces cell growth in RAS mutant cell lines [46–48].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
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      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Mutations in KRAS disrupt the guanine exchange cycle, resulting in KRAS locking in the active GTP-binding state, thereby activating downstream signaling pathways.

    “In short, mutations in KRAS disrupt the guanine exchange cycle, resulting in KRAS “locking” in the active GTP-binding state, thereby activating downstream signaling pathways.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    KRAS mutations are common in a variety of cancers, with 45% of CRC cases in the United States and 49% in China; ∼90% of PDAC in the United States and ∼89% in China; and 35% of LUAD in the United States and ∼13% in China.

    “KRAS mutations are common in a variety of cancers, for example, 45% of CRC cases in the United States and 49% of CRC cases in China; ∼90% of pancreatic ductal adenocarcinoma (PDAC) in the United States, and ∼89% in China; and 35% of lung adenocarcinomas (LUAD, a subtype of non-small-cell lung cancer) in the United States, and ∼13% in China (Fig. 1 for US data) [26].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Hofmann MH, Gerlach D, Misale S, Petronczki M, Kraut N. Expanding the reach of precision oncology by drugging all KRAS mutants. Cancer Discov. 2022;12(4):924–37. source

      Not checked in the free run.

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    Premisecitation

    KRAS proteins primarily bind GDP and are in an inactive conformation maintained by intrinsic GTP hydrolytic activity.

    “KRAS proteins primarily bind to guanosine diphosphate (GDP) and are in an inactive conformation maintained by intrinsic guanosine triphosphate (GTP) hydrolytic activity.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
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      Not checked in the free run.

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      Not checked in the free run.

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    Premisecitation

    The distribution of KRAS mutations varies in different human cancers, with KRAS G12C mutation in 41% of LUAD, whereas KRAS G12D and KRAS G12V are the two most common alleles in CRC and PDAC.

    “The distribution of KRAS mutations varies in different human cancers, with KRAS (G12C) mutation in 41% of LUAD, whereas KRAS (G12D) and KRAS (G12V) are the two most common alleles in CRC and PDAC, as shown in Fig. 1.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Hofmann MH, Gerlach D, Misale S, Petronczki M, Kraut N. Expanding the reach of precision oncology by drugging all KRAS mutants. Cancer Discov. 2022;12(4):924–37. source

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    Premisecitation

    The FDA has approved an allele-specific covalent inhibitor of KRAS G12C, AMG510 (sotorasib), which has marked clinical responses across multiple tumor types.

    “Currently, Food and Drug Administration (FDA) has approved an allele-specific covalent inhibitor of KRAS (G12C), AMG510 (sotorasib) having marked clinical responses across multiple tumor types [21–24].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [21] Janes MR, Zhang J, Li L-S, Hansen R, Peters U, Guo X, et al. Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor. Cell. 2018;172(3):578–89. source

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    • cites [23] Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, et al. KRAS inhibition with Sotorasib in advanced solid tumors. N Engl J Med. 2020;383(13):1207–17. source

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    • cites [24] Kessler D, Gmachl M, Mantoulidis A, Martin LJ, Zoephel A, Mayer M, et al. Drugging an undruggable pocket on KRAS. Proc Natl Acad Sci U S A. 2019;116(32):15823–9. source

      Not checked in the free run.

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    Premisecitation

    Activated KRAS is associated with tumorigenesis, aggressive disease, and poor prognosis.

    “The activated state of KRAS accumulating in vivo results in the activation of downstream signaling pathways and is associated with tumorigenesis, aggressive disease, and poor prognosis [14, 15].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14] Pells S, Divjak M, Romanowski P, Impey H, Hawkins NJ, Clarke AR, et al. Developmentally-regulated expression of murine K-ras isoforms. Oncogene. 1997;15(15):1781–6. source

      Not checked in the free run.

    • cites [15] Drosten M, Dhawahir A, Sum EYM, Urosevic J, Lechuga CG, Esteban LM, et al. Genetic analysis of Ras signalling pathways in cell proliferation, migration and survival. EMBO J. 2010;29(6):1091–104. source

      Not checked in the free run.

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    Premisecitation

    MRTX849 (adagrasib) is a highly selective covalent inhibitor of KRAS G12C and is currently in phase I/II clinical studies.

    “MRTX849 (adagrasib) developed by Mirati Therapeutics, has been identified as a highly selective covalent inhibitor of KRAS (G12C) and is currently in phase I/II clinical studies [44, 45].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [44] Hallin J, Engstrom LD, Hargis L, Calinisan A, Aranda R, Briere DM, et al. The KRAS(G12C) inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. Cancer Discov. 2020;10(1):54–71. source

      Not checked in the free run.

    • cites [45] Jänne PA, Rybkin II, Spira AI, Riely GJ, Papadopoulos KP, Sabari J, et al. KRYSTAL-1: activity and safety of Adagrasib (MRTX849) in advanced/ metastatic non–small-cell lung Cancer (NSCLC) harboring KRAS G12C mutation. Eur J Cancer. 2020;138:S1–2. source

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    Premisecitation

    Other KRAS alleles such as G12R are limited in PDAC.

    “Notably, other KRAS alleles such as G12R are limited in PDAC [26].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Hofmann MH, Gerlach D, Misale S, Petronczki M, Kraut N. Expanding the reach of precision oncology by drugging all KRAS mutants. Cancer Discov. 2022;12(4):924–37. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MRTX1133 binds to the switch-II pocket and inhibits the protein−protein interactions necessary for activation of the downstream pathway of KRAS.

    “MRTX1133 binds to the switch-II pocket and inhibits the protein−protein interactions necessary for the activation of the downstream pathway of KRAS [25] (Table 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Wang X, Allen S, Blake JF, Bowcut V, Briere DM, Calinisan A, et al. Identification of MRTX1133, a noncovalent, potent, and selective KRAS inhibitor. J Med Chem. 2022;65(4):3123–33. source

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    Premisecitation

    NS1 disrupts the self-binding of HRAS and KRAS by directly binding to the α4-α5 interface, reducing activation of downstream pathways and inhibiting cell proliferation.

    “Without interfering with RAS localization and GTPase activity, NS1 disrupts the self-binding of HRAS and KRAS by directly binding to the α4–α5 interface, reducing the activation of downstream pathways and inhibiting cell proliferation [30, 63, 64].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
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      Not checked in the free run.

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    Premisecitation

    MRTX1133 is a potent, selective, noncovalent inhibitor of KRAS G12D with picomolar binding affinity.

    “MRTX1133 was identified as a potent, selective, noncovalent inhibitor of KRAS (G12D) with picomolar binding affinity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Wang X, Allen S, Blake JF, Bowcut V, Briere DM, Calinisan A, et al. Identification of MRTX1133, a noncovalent, potent, and selective KRAS inhibitor. J Med Chem. 2022;65(4):3123–33. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AMG510 is a first-in-class small molecule inhibitor of KRAS G12C that specifically and irreversibly locks KRAS in an inactive GDP binding state.

    “AMG510 is a first-in-class small molecule inhibitor of KRAS (G12C) that specifically and irreversibly locks KRAS in an inactive GDP binding state, as shown in Fig. 2 [41].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Nagasaka M, Li Y, Sukari A, Ou SI, Al-Hallak MN, Azmi AS. KRAS G12C game of thrones, which direct KRAS inhibitor will claim the iron throne? Cancer Treat Rev. 2020;84:101974. source

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  • May combine two claims.

    Premisecitation

    KRAS proteins are featureless, have a nearly spherical structure that lacks a deep hydrophobic pocket, and have no obvious binding site.

    “On the other hand, the KRAS proteins are featureless. They have a nearly spherical structure that lacks a deep hydrophobic pocket and has no obvious binding site [20].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Malumbres M, Barbacid M. RAS oncogenes: the first 30 years. Nat Rev Cancer. 2003;3(6):459–65. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    Although tumor type is driven by KRAS mutations, its codons and the frequency of mutations vary by tissue type.

    “Indeed, although the tumor type is driven by KRAS mutations, its codons and the frequency of mutations vary by tissue type.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The affinity of KRAS and GTP is at the pM level, while the concentration of GTP in cells is up to 0.5 μM.

    “On the one hand, the affinity of KRAS and GTP is at the pM level, while the concentration of GTP in cells is up to 0.5 μM.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [18] Simanshu DK, Nissley DV, McCormick F. RAS proteins and their regulators in human disease. Cell. 2017;170(1):17–33. source

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    • cites [19] Papke B, Der CJ. Drugging RAS: know the enemy. Science. 2017;355(6330):1158–63. source

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    Premisecitation

    Cobimetinib, an oral inhibitor of MEK1 and MEK2, in a clinical trial among 18 patients had an overall response rate of 89% and no acquired drug resistance; after 1 year, 94% of patients maintained progression-free tumors.

    “Diamond et al. validated Cobimetinib, an oral inhibitor of MEK1 and MEK2 in a clinical trial. Among the 18 patients treated, the overall response rate was 89% and there was no acquired drug resistance. After 1 year, 94% of patients maintained the characteristics of progression-free tumors, demonstrating the efficacy of Cobimetinb in treating tumors by acting on the MAPK pathway [68].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Everolimus (RAD001), an allosteric mTOR inhibitor, is approved by the FDA for numerous cancers such as advanced-stage renal cell carcinoma; in the phase III RECORD1 trial, everolimus was associated with prolonged progression-free survival in patients with advanced-stage RCC.

    “Everolimus (RAD001), an allosteric mTOR inhibitor is another derivative of rapamycin approved by the FDA for the treatment of numerous cancers, such as advanced-stage renal cell carcinoma (RCC). In the phase III RECORD1 trial, everolimus was associated with prolonged progression-free survival (PFS) in patients with advanced-stage RCC [80].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] Janku F, Yap TA, Meric-Bernstam F. Targeting the PI3K pathway in cancer: are we making headway? Nat Rev Clin Oncol. 2018;15(5):273–91. source

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  • May combine two claims.

    Premisecitation

    Stimulation of ARS1620-treated cells with epidermal growth factor (EGF) resulted in reactivation of KRAS in the cells, strongly suggesting that EGFR mediates adaptive resistance to KRAS (G12C) inhibitors.

    “Stimulation of ARS1620-treated cells with epidermal growth factor (EGF) resulted in reactivation of KRAS in the cells, strongly suggesting that EGFR mediates adaptive resistance to KRAS (G12C) inhibitors [97].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [97] Akhave NS, Biter AB, Hong DS. Mechanisms of resistance to KRAS-targeted therapy. Cancer Discov. 2021;11(6):1345–52. source

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  • May combine two claims.

    Premisecitation

    BI-3406 binds to the catalytic domain of SOS1 and prevents its interaction with KRAS.

    “Hofmann et al. reported the discovery of a highly efficient, selective, and orally bioavailable small molecule SOS1 inhibitor BI-3406, which binds to the catalytic domain of SOS1 and thus prevents its interaction with KRAS [66].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    RM-018 retains the ability to inhibit KRAS (G12C/Y96D) and may address the problem of drug resistance.

    “RM-018, a neoteric KRAS (G12C) active state inhibitor, retains the ability to inhibit KRAS (G12C/Y96D) and may address the problem of drug resistance [96].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [96] Tanaka N, Lin JJ, Li C, Ryan MB, Zhang J, Kiedrowski LA, et al. Clinical acquired resistance to KRAS inhibition through a novel KRAS switch-II pocket mutation and polyclonal alterations converging on RAS-MAPK reactivation. Cancer Discov. 2021;11(8):1913–22. source

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  • May combine two claims.

    Premisecitation

    TNO155 inhibits MAPK signaling and enhances the efficacy of KRAS G12C inhibitors against KRAS G12C lung and colorectal cancers.

    “The SHP2 inhibitor developed by Novartis, TNO155, inhibits MAPK signaling and enhances the efficacy of KRAS (G12C) inhibitors against KRAS (G12C) lung and colorectal cancers.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Liu C, Lu H, Wang H, Loo A, Zhang X, Yang G, et al. Combinations with allosteric SHP2 inhibitor TNO155 to block receptor tyrosine kinase signaling. Clin Cancer Res. 2021;27(1):342–54. source

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    Premisecitation

    AZD9291 is a novel oral, potent, and selective third-generation irreversible inhibitor that inhibits EGFR T790M resistant mutation without affecting wild-type EGFR.

    “AZD9291, reported by Cross et al., is a novel oral, potent, and selective third-generation irreversible inhibitor that inhibits EGFR (T790M) resistant mutation without affecting wild-type EGFR [71].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014;4(9):1046–61. source

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    Premisecitation

    Unlike NSCLC cell lines, the KRAS (G12C) CRC models have a high basal level of RTK activation and respond to growth factor stimulation.

    “Unlike NSCLC cell lines, the KRAS (G12C) CRC models have a high basal level of RTK activation and respond to growth factor stimulation [99].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [99] Amodio V, Yaeger R, Arcella P, Cancelliere C, Lamba S, Lorenzato A, et al. EGFR blockade reverts resistance to KRAS inhibition in colorectal Cancer. Cancer Discov. 2020;10(8):1129–39. source

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  • May combine two claims.

    Premisecitation

    LC-2 is the first degrading agent capable of degrading endogenous KRAS G12C; it covalently binds KRAS G12C and recruits E3 ligase VHL to rapidly induce KRAS G12C degradation and inhibits MAPK signaling in KRAS G12C mutated cancer cell lines.

    “Bond et al. reported the first degrading agent LC-2 which is capable of degrading endogenous KRAS (G12C) [83]. It covalently binds to KRAS (G12C) and recruits E3 ligase VHL to rapidly induce KRAS (G12C) degradation and inhibits MAPK signaling in KRAS (G12C) mutated cancer cell lines.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [83] Bond MJ, Chu L, Nalawansha DA, Li K, Crews CM. Targeted degradation of oncogenic KRAS(G12C) by VHL-recruiting PROTACs. ACS Cent Sci. 2020;6(8):1367–75. source

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    Premisecitation

    AZD4785 selectively and efficiently reduces the mRNA of KRAS in cells, thereby inhibiting downstream effector pathways and exerting antiproliferative effects in KRAS mutant cells.

    “A chemically modified ASO, AZD4785, selectively and efficiently reduces the mRNA of KRAS in cells, thereby inhibiting the downstream effector pathways and exerting antiproliferative effects in KRAS mutant cells [59].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] Ross SJ, Revenko AS, Hanson LL, Ellston R, Staniszewska A, Whalley N, et al. Targeting KRAS-dependent tumors with AZD4785, a high-affinity therapeutic antisense oligonucleotide inhibitor of KRAS. Sci Transl Med. 2017;9(394):eaal5253. source

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    Premisecitation

    SHP099 inhibits the MAPK signaling pathway, resulting in inhibition of tyrosine kinase receptor-driven proliferation of human cancer cells in vitro and in a mouse tumor transplant model in vivo.

    “SHP099 inhibits the MAPK signaling pathway that results in inhibiting tyrosine kinase receptor-driven proliferation of human cancer cells in vitro and a mouse tumor transplant model in vivo [68].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68] Chen YN, LaMarche MJ, Chan HM, Fekkes P, Garcia-Fortanet J, Acker MG, et al. Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. Nature. 2016;535(7610):148–52. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In Janne's clinical trial of AZD9291, the overall objective tumor response rate was 51%, indicating that AZD9291 was highly effective in patients with EGFR T790M mutant lung cancer whose disease had progressed during previous EGFR tyrosine kinase inhibitor treatment.

    “The overall objective tumor response rate was 51%, indicating that AZD9291 was highly effective in patients with EGFR (T790M) mutant lung cancer whose disease had progressed during previous treatment with EGFR tyrosine kinase inhibitors [71, 72].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [71] Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014;4(9):1046–61. source

      Not checked in the free run.

    • cites [72] Jänne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015;372(18):1689–99. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Bay-293 disrupts the interaction between KRAS and SOS1, interrupts reloading of KRAS and GTP by blocking formation of the KRAS-SOS1 complex, and leads to anti-proliferative activity.

    “Bay-293 can effectively disrupt the interaction between KRAS and its exchange factor SOS1. It interrupts the reloading of KRAS and GTP by blocking the formation of the KRAS-SOS1 complex, leading to anti-proliferative activity [61].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Hillig RC, Sautier B, Schroeder J, Moosmayer D, Hilpmann A, Stegmann CM, et al. Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction. Proc Natl Acad Sci U S A. 2019;116(7):2551–60. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Unlike p110γ and p110δ, p110α is widely expressed and exclusively activated by RAS.

    “Unlike p110γ and p110δ, p110α is widely expressed and exclusively activated by RAS.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [10] Moore AR, Rosenberg SC, McCormick F, Malek S. RAS-targeted therapies: is the undruggable drugged? Nat Rev Drug Discov. 2020;19(8):533–52. source

      Not checked in the free run.

    • cites [79] Verret B, Cortes J, Bachelot T, Andre F, Arnedos M. Efficacy of PI3K inhibitors in advanced breast cancer. Ann Oncol. 2019;30(Suppl_10):x12–20. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a phase I/II study, Gjertsen et al. evaluated the immunogenicity and safety of KRAS peptide vaccine in 17 tumors with KRAS mutations; two of five pancreatic cancer patients showed proliferative T cell responses, with a longer median survival of 10.5 months.

    “In a phase I/II study, Gjertsen et al. have evaluated the immunogenicity and safety of KRAS peptide vaccine in 17 tumors with KRAS mutations. Two of the five patients with pancreatic cancer showed proliferative T cell responses, with a longer median survival of 10.5 months [90].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [90] Gjertsen MK, Buanes T, Rosseland AR, Bakka A, Gladhaug I, Søreide O, et al. Intradermal ras peptide vaccination with granulocyte-macrophage colony-stimulating factor as adjuvant: clinical and immunological responses in patients with pancreatic adenocarcinoma. Int J Cancer. 2001;92(3):441–50. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both the T cell pools of healthy individuals and cancer patients contain T cells that can identify KRAS mutation; after vaccination those T cells can be selectively expanded in tumor patients.

    “Both the T cell pools of healthy individuals and cancer patients contain T cells that can identify KRAS mutation. After vaccination those T cells can be selectively expanded in tumor patients.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [84] Mukherji B, Chakraborty NG, Yamasaki S, Okino T, Yamase H, Sporn JR, et al. Induction of antigen-specific cytolytic T cells in situ in human melanoma by immunization with synthetic peptide-pulsed autologous antigen presenting cells. Proc Natl Acad Sci U S A. 1995;92(17):8078–82. source

      Not checked in the free run.

    • cites [85] Hsu FJ, Benike C, Fagnoni F, Liles TM, Czerwinski D, Taidi B, et al. Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nat Med. 1996;2(1):52–8. source

      Not checked in the free run.

    • cites [86] Nestle FO, Alijagic S, Gilliet M, Sun Y, Grabbe S, Dummer R, et al. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med. 1998;4(3):328–32. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BI-3406 attenuates MEK-in feedback reactivation, enhancing the sensitivity of KRAS-mutant cancers to MEK inhibition.

    “Most importantly, BI-3406 also attenuates MEK-in feedback reactivation, thereby enhancing the sensitivity of KRAS-mutant cancers to MEK inhibition [66].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Hofmann MH, Gmachl M, Ramharter J, Savarese F, Gerlach D, Marszalek JR, et al. BI-3406, a potent and selective SOS1-KRAS interaction inhibitor, is effective in KRAS-driven cancers through combined MEK inhibition. Cancer Discov. 2021;11(1):142–57. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Xue et al. found increased new KRAS (G12C) protein in KRAS (G12C)-mutant tumor cells and elucidated that EGFR can promote the conversion of KRAS from the GDP state to the GTP-bound state and AURKA can maintain its active state by binding to KRAS.

    “Xue et al. found the increased new KRAS (G12C) protein in KRAS (G12C)-mutant tumor cells and elucidate that EGFR can promote the conversion of KRAS from the GDP state to the GTP-bound state (activated state) and AURKA can maintain its active state by binding to KRAS [7].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Xue JY, Zhao Y, Aronowitz J, Mai TT, Vides A, Qeriqi B, et al. Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition. Nature. 2020;577(7790):421–5. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Most patients with KRAS (G12C) in NSCLC benefit from selective KRAS (G12C) inhibition, whereas CRC patients with the same mutation rarely respond to KRAS (G12C) inhibition.

    “Most patients with KRAS (G12C) in NSCLC benefit from selective KRAS (G12C) inhibition, whereas CRC patients with the same mutation rarely respond to KRAS (G12C) inhibition [99].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [99] Amodio V, Yaeger R, Arcella P, Cancelliere C, Lamba S, Lorenzato A, et al. EGFR blockade reverts resistance to KRAS inhibition in colorectal Cancer. Cancer Discov. 2020;10(8):1129–39. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cetuximab sensitizes the KRAS (G12C) CRC cells to AMG510, and the combination restores secondary resistance to anti-EGFR antibodies.

    “Cetuximab sensitizes the KRAS (G12C) CRC cells to AMG510, and the combination restores secondary resistance to anti-EGFR antibodies.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [102] Saltz LB, Meropol NJ, Loehrer PJ, Needle MN, Kopit J, Mayer RJ. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol. 2004;22(7):1201–8. source

      Not checked in the free run.

    • cites [103] Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007;25(13):1658–64. source

      Not checked in the free run.

    • cites [104] Díaz-Serrano A, Gella P, Jiménez E, Zugazagoitia J, Paz-Ares Rodríguez L. Targeting EGFR in lung Cancer: current standards and developments. Drugs. 2018;78(9):893–911. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SHP2 inhibitors can restore the sensitivity of KRAS-mutant NSCLC to MEK inhibition and increase inactive GDP-bound KRAS.

    “SHP2 inhibitors can restore the sensitivity of KRAS-mutant NSCLC to MEK inhibition and increase inactive GDP-bound KRAS.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [7] Xue JY, Zhao Y, Aronowitz J, Mai TT, Vides A, Qeriqi B, et al. Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition. Nature. 2020;577(7790):421–5. source

      Not checked in the free run.

    • cites [97] Akhave NS, Biter AB, Hong DS. Mechanisms of resistance to KRAS-targeted therapy. Cancer Discov. 2021;11(6):1345–52. source

      Not checked in the free run.

    • cites [107] Mainardi S, Mulero-Sánchez A, Prahallad A, Germano G, Bosma A, Krimpenfort P, et al. SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo. Nat Med. 2018;24(7):961–7. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Amplified MET increases the active form of RAS and also enhances AKT activation in the absence of RAS.

    “Amplified MET increases the active form of RAS. Besides, MET also enhances AKT activation in the absence of RAS [112].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [112] Suzuki S, Yonesaka K, Teramura T, Takehara T, Kato R, Sakai H, et al. KRAS inhibitor resistance in -amplified non-small cell lung Cancer induced by RAS- and non-RAS-mediated cell signaling mechanisms. Clin Cancer Res. 2021;27(20):5697–707. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    FAK inhibition may enhance KRAS (G12C) inhibition and immunotherapy.

    “Thus, FAK inhibition may enhance KRAS (G12C) inhibition and immunotherapy [125, 126].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [125] Jiang H, Hegde S, Knolhoff BL, Zhu Y, Herndon JM, Meyer MA, et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat Med. 2016;22(8):851–60. source

      Not checked in the free run.

    • cites [126] Serrels A, Lund T, Serrels B, Byron A, McPherson RC, von Kriegsheim A, et al. Nuclear FAK controls chemokine transcription, Tregs, and evasion of anti-tumor immunity. Cell. 2015;163(1):160–73. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FAK-related fibrosis can form a barrier in tumors that limits the CD8+ T cells infiltration in tumors, and FAK inhibition can ultimately promote the antitumor effects by decreasing the number of tumor-resident Tregs.

    “FAK-related fibrosis can form a barrier in tumors that limits the CD8+ T cells infiltration in tumors, and FAK inhibition can ultimately promote the antitumor effects by decreasing the number of tumor-resident Tregs.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [125] Jiang H, Hegde S, Knolhoff BL, Zhu Y, Herndon JM, Meyer MA, et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat Med. 2016;22(8):851–60. source

      Not checked in the free run.

    • cites [126] Serrels A, Lund T, Serrels B, Byron A, McPherson RC, von Kriegsheim A, et al. Nuclear FAK controls chemokine transcription, Tregs, and evasion of anti-tumor immunity. Cell. 2015;163(1):160–73. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Inhibition of oncogenic KRAS disengages the NF1/RSK1 negative feedback pathway, leading to WT RAS activation and triggering adaptive drug resistance.

    “Consequently, inhibition of oncogenic KRAS disengages this negative feedback pathway, leading to WT RAS activation and triggering adaptive drug resistance [105].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [105] Cheng DK, Oni TE, Thalappillil JS, Park Y, Ting H-C, Alagesan B, et al. Oncogenic KRAS engages an RSK1/NF1 pathway to inhibit wild-type RAS signaling in pancreatic cancer. Proc Natl Acad Sci U S A. 2021;118(21):e2016904118. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Canon et al. suggested that AMG510 treatment resulted in increased T cell priming and antigen recognition and promoted the establishment of long-term T cell responses.

    “Canon et al. suggested that AMG510 treatment resulted in increased T cell priming and antigen recognition and promoted the establishment of long-term T cell responses [42].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019;575(7781):217–23. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Histone deacetylase 5 (HDAC5)-induced bypass promotes macrophage recruitment into the TME and enables tumor recurrence following the extinction of KRAS (G12D).

    “Histone deacetylase 5 (HDAC5)-induced bypass promotes macrophage recruitment into the TME and enables tumor recurrence following the extinction of KRAS (G12D) [146].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [146] Hou P, Kapoor A, Zhang Q, Li J, Wu C-J, Li J, et al. Tumor microenvironment remodeling enables bypass of oncogenic KRAS dependency in pancreatic Cancer. Cancer Discov. 2020;10(7):1058–77. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inhibition of the FGFR signaling pathway reduces ERK and mTOR activation, whereas AXL inhibition attenuates the activation of PI3K pathway.

    “Inhibition of the FGFR signaling pathway reduces ERK and mTOR activation, whereas AXL inhibition attenuates the activation of PI3K pathway [43, 136–139].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [43] Zhang Z, Lee JC, Lin L, Olivas V, Au V, LaFramboise T, et al. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat Genet. 2012;44(8):852–60. source

      Not checked in the free run.

    • cites [136] Byers LA, Diao L, Wang J, Saintigny P, Girard L, Peyton M, et al. An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance. Clin Cancer Res. 2013;19(1):279–90. source

      Not checked in the free run.

    • cites [137] Raoof S, Mulford IJ, Frisco-Cabanos H, Nangia V, Timonina D, Labrot E, et al. Targeting FGFR overcomes EMT-mediated resistance in EGFR mutant non-small cell lung cancer. Oncogene. 2019;38(37):6399–413. source

      Not checked in the free run.

    • cites [138] Salt MB, Bandyopadhyay S, McCormick F. Epithelial-to-mesenchymal transition rewires the molecular path to PI3K-dependent proliferation. Cancer Discov. 2014;4(2):186–99. source

      Not checked in the free run.

    • cites [139] Guix M, Faber AC, Wang SE, Olivares MG, Song Y, Qu S, et al. Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. J Clin Invest. 2008;118(7):2609–19.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Combining AMG510 with anti-PD-1 or anti-PD-L1 therapy augmented T cell infiltration and achieved longer-term efficacy.

    “Combining AMG510 with anti-PD-1 or anti-PD-L1 therapy augmented T cell infiltration and achieve longer-term efficacy [42, 50, 150].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [42] Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019;575(7781):217–23. source

      Not checked in the free run.

    • cites [50] Skoulidis F, Byers LA, Diao L, Papadimitrakopoulou VA, Tong P, Izzo J, et al. Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov. 2015;5(8):860–77. source

      Not checked in the free run.

    • cites [150] Skoulidis F, Goldberg ME, Greenawalt DM, Hellmann MD, Awad MM, Gainor JF, et al. Mutations and PD-1 inhibitor resistance in -mutant lung adenocarcinoma. Cancer Discov. 2018;8(7):822–35. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AMG510-resistant tumors have significantly reduced adaptive immune cell populations and become immunologically "cold" with dynamic and diverse remodeling patterns within the TME, such as alterations in angiogenesis, coagulation pathways, and fatty acid metabolism.

    “It has been shown that AMG510-resistant tumors have significantly reduced adaptive immune cell populations and become immunologically “cold” with dynamic and diverse remodeling patterns within the TME, such as alterations in angiogenesis, coagulation pathways, and fatty acid metabolism [149].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [149] Tsai YS, Woodcock MG, Azam SH, Thorne LB, Kanchi KL, Parker JS, et al. Rapid idiosyncratic mechanisms of clinical resistance to KRAS G12C inhibition. J Clin Invest. 2022;132(4):e155523. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hallin et al. illustrated that genetic alterations in cell cycle regulators resulted in cell cycle dysregulation and changed KRAS mutant allele frequency, identifying additional factors that could attenuate the therapeutic response to MRTX849.

    “Hallin et al. illustrated that genetic alterations in cell cycle regulators resulted in cell cycle dysregulation and changed KRAS mutant allele frequency, identifying additional factors that could attenuate the therapeutic response to MRTX849 [60].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Hallin J, Engstrom LD, Hargis L, Calinisan A, Aranda R, Briere DM, et al. The KRAS inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. Cancer Discov. 2020;10(1):54–71. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In CRC, only 1 of 12 patients had a partial response and 10 patients had stable disease with AMG510.

    “However, only 1 of 12 patients had a PR and 10 patients had SD in CRC [23].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, et al. KRAS inhibition with Sotorasib in advanced solid tumors. N Engl J Med. 2020;383(13):1207–17. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    According to the results of AMG510 in the phase I trial, this KRAS (G12C) inhibitor is effective in NSCLC (NCT03600883): 7 out of the 13 patients had a partial response (PR) and 6 had stable disease (SD).

    “According to the results of AMG510 in the phase I trial, this KRAS (G12C) inhibitor is effective in NSCLC (NCT03600883). 7 out of the 13 patients had a partial response (PR) and 6 had stable disease (SD).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, et al. KRAS inhibition with Sotorasib in advanced solid tumors. N Engl J Med. 2020;383(13):1207–17. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    USP21 is expected to be a viable therapeutic target in PDAC, either as monotherapy or in combination with inhibitors targeting KRAS mutation.

    “Therefore, USP21 is expected to be a viable therapeutic target in PDAC, either as monotherapy or in combination with inhibitors targeting KRAS mutation [51, 52].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [51] Hou P, Ma X, Zhang Q, Wu C-J, Liao W, Li J, et al. USP21 deubiquitinase promotes pancreas cancer cell stemness via Wnt pathway activation. Genes Dev. 2019;33(19–20):1361–6. source

      Not checked in the free run.

    • cites [52] Pannu J, Belle JI, Förster M, Duerr CU, Shen S, Kane L, et al. Ubiquitin specific protease 21 is dispensable for normal development, hematopoiesis and lymphocyte differentiation. Plos One. 2015;10(2):e0117304. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    CRC is more difficult to treat than NSCLC, suggesting that CRC will require combination therapy.

    “Therefore, CRC is more difficult to treat than NSCLC, suggesting that CRC will require combination therapy.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, et al. KRAS inhibition with Sotorasib in advanced solid tumors. N Engl J Med. 2020;383(13):1207–17. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Vetter et al. mention that different KRAS mutations are grouped into four categories based on their effects on GTP hydrolysis, nucleotide exchange, and effector protein interactions.

    “Vetter et al. mention that different KRAS mutations are grouped into four categories based on their effects on GTP hydrolysis, nucleotide exchange, and effector protein interactions [152].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [152] Vetter IR, Wittinghofer A. The guanine nucleotide-binding switch in three dimensions. Science. 2001;294(5545):1299–304. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Overexpression of wild-type KRAS significantly stimulated cell migration, which is further promoted by KRAS (G12V).

    “The overexpression of wild-type KRAS significantly stimulated cell migration, which is further promoted by KRAS (G12V) [54, 55].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [54] Choi BH, Chen C, Philips M, Dai W. RAS GTPases are modified by SUMOylation. Oncotarget. 2018;9(4):4440–50. source

      Not checked in the free run.

    • cites [55] Choi BH, Philips MR, Chen Y, Lu L, Dai W. K-Ras Lys-42 is crucial for its signaling, cell migration, and invasion. J Biol Chem. 2018;293(45):17574–81. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In preclinical studies, possible resistance mechanisms for KRAS mutation therapy include secondary mutations in the KRAS binding site, reactivation of multiple upstream and downstream effectors, cell-cycle dysregulation, and immune deficiency.

    “In preclinical studies, possible resistance mechanisms for KRAS mutation therapy include secondary mutations in the KRAS binding site, reactivation of multiple upstream and downstream effectors, cell-cycle dysregulation, and immune deficiency [94, 95].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [94] Awad MM, Liu S, Rybkin II, Arbour KC, Dilly J, Zhu VW, et al. Acquired resistance to KRAS inhibition in Cancer. N Engl J Med. 2021;384(25):2382–93. source

      Not checked in the free run.

    • cites [95] Koga T, Suda K, Fujino T, Ohara S, Hamada A, Nishino M, et al. KRAS secondary mutations that confer acquired resistance to KRAS G12C inhibitors, Sotorasib and Adagrasib, and overcoming strategies: insights from in vitro experiments. J Thorac Oncol. 2021;16(8):1321–32. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In phase I/II clinical trials (NCT03785249), three out of the five NSCLC patients achieved a PR, and one of two patients with CRC achieved a PR.

    “In phase I/II clinical trials (NCT03785249), three out of the five NSCLC patients achieved a PR, and one of two patients with CRC patients achieved a PR [94].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [94] Awad MM, Liu S, Rybkin II, Arbour KC, Dilly J, Zhu VW, et al. Acquired resistance to KRAS inhibition in Cancer. N Engl J Med. 2021;384(25):2382–93. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    The main drivers of resistance include secondary mutations of KRAS itself, reactivation of multiple MAPK effectors from upstream and downstream of KRAS, immunodeficiency, etc.

    “The main drivers include secondary mutations of KRAS itself, reactivation of multiple MAPK effectors from upstream and downstream of KRAS, immunodeficiency, etc.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Combination therapy has always been more toxic, with poor safety, and will bring more financial burden to patients.

    “Moreover, combination therapy has always been more toxic, with poor safety, and combination therapy will bring more financial burden to patients [10].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Moore AR, Rosenberg SC, McCormick F, Malek S. RAS-targeted therapies: is the undruggable drugged? Nat Rev Drug Discov. 2020;19(8):533–52. source

      Not checked in the free run.

57 of 57

  • The paper relies on this without support.

    Resistance to monotherapy of KRAS inhibitors is eventually developed.

    “Despite such inhibitors showing remarkable clinical responses, resistance to monotherapy of KRAS inhibitors is eventually developed.”

  • The paper relies on this without support.

    Significant progress has been made in understanding the mechanisms of drug resistance to KRAS-mutant inhibitors.

    “Significant progress has been made in understanding the mechanisms of drug resistance to KRAS-mutant inhibitors.”

  • The paper relies on this without support.

    Clinical studies have shown effective CD4+ and CD8+ T cell responses to KRAS mutation tumors.

    “Clinical studies have shown effective CD4+ and CD8+ T cell responses to KRAS mutation tumors.”

  • The paper relies on this without support.

    Previous studies have shown that antisense oligonucleotides (ASO) are an attractive treatment for KRAS-driven human cancers, and therefore deserve further development.

    “Previous studies have shown that antisense oligonucleotides (ASO) are an attractive treatment for KRAS-driven human cancers, and therefore deserve further development.”

  • The paper relies on this without support.

    FAK is a biomarker of the aberrant KRAS signaling pathway, and it responds to the administration of KRAS (G12C) inhibitors.

    “FAK is a biomarker of the aberrant KRAS signaling pathway, and it responds to the administration of KRAS (G12C) inhibitors.”

  • The paper relies on this without support.

    Both aberrant FAK-YAP signaling and FAK-related fibrogenesis affect the development of resistance to KRAS (G12C) inhibitors.

    “Both aberrant FAK-YAP signaling and FAK-related fibrogenesis affect the development of resistance to KRAS (G12C) inhibitors.”

  • The paper relies on this without support.

    Sustained activation of FAK is induced by KRAS (G12C) inhibition, leading to attenuated treatment outcomes by dysregulating FAK-YAP signaling and fibrosis formation.

    “In short, sustained activation of FAK is induced by KRAS (G12C) inhibition, leading to attenuated treatment outcomes by dysregulating FAK-YAP signaling and fibrosis formation (Fig. 4).”
7 of 7

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?

  • KRAS-mutant tumors are often insensitive to KRAS-targeted therapy due to feedback reactivation of upstream RTKs.

    “KRAS-mutant tumors are often insensitive to KRAS-targeted therapy due to feedback reactivation of upstream RTKs, which are crucial for cancer cell signaling [62, 63].”

    From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [62]

    The section on feedback activation in ‘Mechanisms of resistance to KRAS-mutant targeting therapy and combination therapy’ says upstream signaling, including EGFR, can attenuate KRAS-inhibitor efficacy and contribute to adaptive resistance. But it does not establish that KRAS-mutant tumors generally are often insensitive for this reason: it says most patients with KRAS(G12C) NSCLC benefit from inhibition, while those with KRAS(G12C) colorectal cancer rarely respond. Page numbers are unavailable in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • A significant challenge with KRAS inhibitors is that the majority of patients do not respond, and initial responders will inevitably encounter disease progression.

    “Furthermore, a significant challenge with KRAS inhibitors is that the majority of patients do not respond to such treatments, and initial responders will inevitably encounter disease progression. 9-12”

    From Anti-tumor efficacy of HRS-4642 and its potential combination with proteasome inhibition in KRAS G12D-mutant cancer (2024) · cites this paper as [12]

    The Abstract says resistance to KRAS-inhibitor monotherapy eventually develops, supporting the progression concern. But the Mechanisms of resistance section says most patients with KRAS (G12C) NSCLC benefit from inhibition, while CRC patients rarely respond; it does not support the unqualified claim that a majority of patients do not respond. Page numbers were not provided in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • However, the rapid emergence of adaptive resistance and reactivation of MAPK signaling following treatment necessitates the development of KRAS-targeted drugs utilizing TPD technologies, such as PROTACs.

    “However, the rapid emergence of adaptive resistance and reactivation of MAPK signaling following treatment necessitates the development of KRAS-targeted drugs utilizing TPD technologies, such as PROTACs.484”

    From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [484]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • SHP2 inhibitor has two different names

    Minor

    The prose lists the SHP2 inhibitor as RC-4630, while Table 2 names it RMC-4630.

  • ERK inhibitor name and code disagree

    Minor

    The prose calls the inhibitor Ulititinib (BFD − 523), whereas its cited reference names it Ulixertinib (BVD-523).

  • Desai study is assigned the wrong drug

    Minor

    The text says Desai et al. evaluated sorafenib, but the cited study's title identifies its study drug as lifirafenib (BGB-283).

  • CRC T-cell-transfer claim conflicts with its cited reference

    Minor

    The statement attributes a metastatic CRC adoptive T-cell-transfer result to Chaft et al. [92], but reference 92 describes a KRAS vaccine study in stage I-III lung adenocarcinoma.

  • Cobimetinib trial conflicts with its cited reference

    Minor

    The Cobimetinib trial statement cites reference 68, but reference 68 is attributed to Chen et al. and concerns SHP2 inhibition, not a Cobimetinib trial by Diamond et al.

5 of 5

The citation lists haven’t been fetched yet

References 155 · Cited by 231

Research works printed but not linked: 1

  1. Hallin J, Engstrom LD, Hargis L, Calinisan A, Aranda R, Briere DM, et al. The KRAS inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. Cancer Discov. 2020;10(1):54–71. · DOI · Paper page

Authors
Zhu, C., Guan, X., Zhang, X., Luan, X., Song, Z., Cheng, X., Zhang, W., & Qin, J.-J.
Affiliations
  • Zhejiang Cancer Hospital (CN)
  • Shanghai University of Traditional Chinese Medicine (CN)
  • Second Military Medical University (CN)
Corresponding author
  • Cheng, Xiangdong
  • Zhang, Weidong
  • Qin, Jiang-Jiang
ORCID
Venue
Molecular Cancer
Publisher
Springer Science and Business Media LLC
Published
2022-08-04
Volume
21
Issue
1
Pages
159-159
ISSN
1476-4598 (ISSN-L)
DOI
10.1186/s12943-022-01629-2
PMC
PMC9351107
OpenAlex
W4289711071
Semantic Scholar
1c209a825d4566e1d74e7cfa93234c716e797d42
Cited by
231
References
155
Citations by year
2026: 49 · 2025: 67 · 2024: 74 · 2023: 35 · 2022: 4
FWCI
4.68
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Cancer (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province (2022E10021)
  • National Key Research and Development Program of China (2021YFA0910100)
  • Shanghai Frontiers Science Center of TCM Chemical Biology, and Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (ZYYCXTD-D-202004)
  • Medical Science and Technology Project of Zhejiang Province (WKJ-ZJ-2202)
  • Program of Zhejiang Provincial TCM Sci-tech Plan (2020ZZ005)
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 mutation, KRAS G12C inhibitors, drug resistance mechanisms, combination therapy
MeSH terms
Drug Resistance, Humans, Mutation, Neoplasms, Proto-Oncogene Proteins p21(ras)

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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