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Cited by 129Lung Cancer Treatments and MutationsProtein Kinase Regulation and GTPase SignalingLung Cancer Research Studies

New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness

Open access
Yang, Haitang, Liang, Shun-Qing, Schmid, Ralph A., Peng, Ren-Wang·2019·Frontiers in Oncology
DOI 10.3389/fonc.2019.00953PMC PMC6773824
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Abstract

In non-small cell lung cancer (NSCLC), the most frequent oncogenic mutation in western countries is KRAS, which, however, remains no clinically approved targeted therapies. Recent progress on high biological heterogeneity including diverse KRAS point mutations, varying dependence on mutant KRAS, wide spectrum of other co-occurring genetic alterations, as well as distinct cellular status across the epithelial-to-mesenchymal transition (EMT), has not only deepened our understanding about the pathobiology of KRAS-mutant NSCLC, but also brought about unprecedented new hopes for precision treatment of patients. In this review, we update most recent advances in KRAS-mutant lung cancer, with a focus on mechanistic insights into tumor heterogeneity, the potential clinic implications and new therapies on horizons tailored for KRAS-mutant lung cancer.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review summarizes how heterogeneity in KRAS-mutant NSCLC—diverse KRAS point mutations, variable KRAS dependence and EMT status, and co-occurring alterations—complicates treatment. It highlights emerging direct KRASG12C inhibitors and combination strategies targeting MEK, SHP2, autophagy, ERBB, C-RAF, chemotherapy resistance, and immunotherapy, emphasizing molecular stratification beyond KRAS mutation status.

Key findings

  • KRAS mutation accounts for ~30% of lung adenocarcinomas in western countries and about 10% of Asian lung adenocarcinomas; most mutations occur in codon 12, and co-occurring alterations in TP53, CDKN2A/2B, STK11, and KEAP1 define biologically and therapeutically distinct subgroups.
  • Direct KRASG12C targeting showed early clinical activity: in a phase I trial of AMG510 in 32 patients with KRASG12C mutation (14 NSCLC, 19 colorectal, 2 appendix), 5 of 10 evaluable NSCLC patients had partial response and 4 had stable disease, for a disease control rate of 90% (9/10); 13 of 18 evaluable colorectal cancer patients had stable disease, with primarily grade 1 events (68%) and two grade 3 treatment-related AEs.
  • MEK inhibitor combinations have had mixed results: a phase II trial of selumetinib plus docetaxel reported median OS 9.4 vs. 5.2 months (HR 0.80, 80% CI 0.56–1.14; one-sided p=0.21), median PFS 5.3 vs. 2.1 months (HR 0.58, 80% CI 0.42–0.79; one-sided p=0.014), and response rate 37% vs. 0% (p<0.0001), whereas the phase III SELECT-1 trial showed median PFS 3.9 vs. 2.8 months (HR 0.93, 95% CI 0.77–1.12; P=0.44) and median OS 8.7 vs. 7.9 months (HR 1.05, 95% CI 0.85–1.30; P=0.64).
  • Co-mutations and immunotherapy response are heterogeneous: co-mutated KEAP1 was an independent marker of poorer survival (HR=1.96; P<0.001) and less response to chemotherapy (HR=1.64; P=0.03) and immune therapy (HR=3.54; P=0.003); among 377 non-squamous NSCLC patients, STK11 alterations (N=102) were associated with shorter PFS (4.8 vs. 7.2 months, HR 1.5, 95% CI 1.1–2.0; P=0.0063) and OS (10.6 vs. 16.7 months, HR 1.58, 95% CI 1.09–2.27; P=0.0083), and adding pembrolizumab did not significantly improve PFS or OS; a meta-analysis found immune checkpoint inhibitors prolonged OS in KRAS-mutant (HR 0.65, 95% CI 0.44–0.97; P=0.03) but not KRAS wild-type patients (HR 0.86, 95% CI 0.67–1.11; P=0.24).

Methods

  • Narrative review; no primary patient cohort or systematic review protocol is stated. It synthesizes published mechanistic, preclinical, and clinical literature on KRAS-mutant lung cancer.
  • Includes a pooled drug sensitivity analysis based on the Genomics of Drug Sensitivity in Cancer dataset, comparing KRAS-mutant (n=20) with KRAS-wild-type (n=40) lung adenocarcinoma cells; figures also draw on TCGA primary lung adenocarcinoma (n=489), TCGA squamous cell carcinoma (n=492), and MSKCC primary (n=471) and metastatic (n=444) lung adenocarcinoma cohorts.

Limitations

  • Not stated in the paper: the review does not include a limitations section.
  • Evident from the text: it is a narrative review without stated systematic search or inclusion criteria; many cited therapeutic strategies are preclinical or early-phase, and the text repeatedly notes tumor heterogeneity, inconsistent trial outcomes, and that specific efficacy in KRAS-mutant NSCLC remains to be investigated.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3389/fonc.2019.00953

Cites

103 of 103 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 207 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Heterogeneity in KRAS-mutant tumors arises from co-occurring alterations of other genes, e.g., TP53, CDKN2A/2B, STK11, and KEAP1.

    “Heterogeneity in KRAS-mutant tumors also arises from co-occurring alterations of other genes, e.g., TP53, CDKN2A/2B, STK11, and KEAP1 (Figure 2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Figure 2

      Not checked in the free run.

  • Findingown data

    In the authors' pooled drug sensitivity analysis of publicly available Genomics of Drug Sensitivity in Cancer data, KRAS-mutant lung cancer cells are exclusively more sensitive to various MEK inhibitors rather than inhibitors targeting other oncogenic pathways, compared with KRAS-wild-type lung cancer cells.

    “we performed pooled drug sensitivity analysis based on publicly available dataset in Genomics of Drug Sensitivity in Cancer, which revealed that, compared with KRAS-wild-type lung cancer cells, KRAS-mutant lung cancer cells are exclusively more sensitive to various MEK inhibitors rather than those targeting other oncogenic pathways (Figure 3).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Figure 3

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  • Premisecitation

    In genetically engineered mouse models, KrasG12C tumors were significantly more sensitive to MEK inhibitor than KrasG12D tumors.

    “studies with genetically engineered mouse model showed that KrasG12C tumors were significantly more sensitive to MEK inhibitor than the KrasG12D ones”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Li, 2018, Assessing therapeutic efficacy of MEK inhibition in a KRAS(G12C)-driven mouse model of lung cancer, Clin Cancer Res. source

      Not checked in the free run.

  • Premisecitation

    In KRAS-mutant lung cancer, tumors carrying KRASG12C exhibited higher ERK1/2 phosphorylation than those with KRASG12D.

    “In KRAS-mutant lung cancer, tumors carrying KRASG12C exhibited higher ERK1/2 phosphorylation than those with KRASG12D (17).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Li, 2018, Assessing therapeutic efficacy of MEK inhibition in a KRAS(G12C)-driven mouse model of lung cancer, Clin Cancer Res. source

      Not checked in the free run.

  • Premisecitation

    KRAS mutation is the most frequent oncogenic mutation in non-small cell lung cancer in western countries.

    “In non-small cell lung cancer (NSCLC), the most frequent oncogenic mutation in western countries is KRAS”
    • Also stated in: § Introduction · plain
      “Carcinogenic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation is the most common gain-of-function alteration”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Dearden, 2013, Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap), Ann Oncol. source

      Not checked in the free run.

  • May combine two claims. 53
  • Classified as probably not a substantial claim. 12

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    Findingown data

    In lung cancer, KRAS mutations occur primarily in adenocarcinoma and only rarely in squamous cell carcinoma.

    “In lung cancer, KRAS mutations occur primarily in adenocarcinoma, whereas they are only rarely seen in squamous cell carcinoma (Figure 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Figure 1

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Diverse point mutations exist within KRAS, the majority affect codon 12 in NSCLC, leading to amino acid substitutions that impair intrinsic hydrolytic activity and render KRAS constitutively active.

    “Diverse point mutations exist within KRAS, the majority of which affect codon 12 of the protein in NSCLC (Figure 1), leading to amino acid substitutions that impair the intrinsic hydrolytic activity and render the KRAS oncoprotein constitutively active.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Figure 1

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

    Premisecitation

    In patients with lung cancer harboring KRAS mutations, most mutations occur in codon 12, whereas mutations in codons 13 and 61 are less frequent.

    “In patients with lung cancer harboring KRAS mutations, the most mutations occur in codon 12, whereas mutations in codons 13 and 61 are less frequent (4).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Riely, 2009, KRAS mutations in non-small cell lung cancer, Proc Am Thorac Soc. source

      Not checked in the free run.

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    Premisecitation

    The presence of KRAS amino acid substitution influences patients' prognosis and is negatively associated with response to targeted therapy and chemotherapy.

    “In lung cancer, the presence of KRAS amino acid substitution influences patients' prognosis and is negatively associated with patient response to targeted therapy (7, 8) and chemotherapy (9–11).”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [7] Rulli, 2015, Value of KRAS as prognostic or predictive marker in NSCLC: results from the TAILOR trial, Ann Oncol. source

      Not checked in the free run.

    • cites [8] Papadimitrakopoulou, 2016, The BATTLE-2 study: a biomarker-integrated targeted therapy study in previously treated patients with advanced non-small-cell lung cancer, J Clin Oncol. source

      Not checked in the free run.

    • cites [9] Garassino, 2011, Different types of K-Ras mutations could affect drug sensitivity and tumour behaviour in non-small-cell lung cancer, Ann Oncol. source

      Not checked in the free run.

    • cites [10] Park, 2017, KRAS G12C mutation as a poor prognostic marker of pemetrexed treatment in non-small cell lung cancer, Korean J Intern Med. source

      Not checked in the free run.

    • cites [11] Renaud, 2018, KRAS-specific amino acid substitutions are associated with different responses to chemotherapy in advanced non-small-cell lung cancer, Clin Lung Cancer. source

      Not checked in the free run.

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    Premisecitation

    Compared to wild-type KRAS, mutant KRASG12C or KRASG12V is less dependent on AKT, which is more intimately engaged by other mutant KRAS proteins.

    “Specifically, compared to wild-type KRAS, the mutant KRASG12C or KRASG12V is less dependent on AKT, which, however, is more intimately engaged by other mutant KRAS proteins.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Ihle, 2012, Effect of KRAS oncogene substitutions on protein behavior: implications for signaling and clinical outcome, J Natl Cancer Inst. source

      Not checked in the free run.

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

    Premisecitation

    KRAS switches between active GTP-bound and inactive GDP-bound status, regulated by guanine nucleotide exchange factors and GTPase-activating proteins.

    “KRAS switches between the active GTP-bound and inactive GDP-bound status, which is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), respectively (3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Kranenburg, 2005, The KRAS oncogene: past, present, and future, Biochim Biophys Acta. source

      Not checked in the free run.

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

    Premisecitation

    KRAS mutation accounts for about 10% of Asian lung adenocarcinomas.

    “about 10% of Asian lung adenocarcinomas (2)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Dearden, 2013, Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap), Ann Oncol. source

      Not checked in the free run.

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    Premisecitation

    Mutant KRAS with different amino acid substitutions may associate with distinct biological behavior and can lead to different clinical outcomes.

    “Mutant KRAS with different amino acid substitutions may also associate with distinct biological behavior (13) and can lead to different clinical outcomes (14–16).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [13] Renaud, 2016, Specific KRAS amino acid substitutions and EGFR mutations predict site-specific recurrence and metastasis following non-small-cell lung cancer surgery, Br J Cancer. source

      Not checked in the free run.

    • cites [14] Yu, 2015, Prognostic impact of KRAS mutation subtypes in 677 patients with metastatic lung adenocarcinomas, J Thorac Oncol. source

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    • cites [15] Fu, 2019, KRAS G12V mutation is an adverse prognostic factor of Chinese gastric cancer patients, J Cancer. source

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    • cites [16] Wiesweg, 2019, Impact of RAS mutation subtype on clinical outcome-a cross-entity comparison of patients with advanced non-small cell lung cancer and colorectal cancer, Oncogene. source

      Not checked in the free run.

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

    Premisecitation

    KRAS mutation accounts for approximately 30% of lung adenocarcinomas in western countries.

    “accounting for ~30% of lung adenocarcinomas in western countries”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Dearden, 2013, Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap), Ann Oncol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MEK inhibition significantly increased chemotherapeutic efficacy and progression-free survival of KRASG12C mice.

    “MEK inhibition significantly increased chemotherapeutic efficacy and progression-free survival (PFS) of KRASG12C mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Li, 2018, Assessing therapeutic efficacy of MEK inhibition in a KRAS(G12C)-driven mouse model of lung cancer, Clin Cancer Res. source

      Not checked in the free run.

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    Premisecitation

    The two KRAS-mutant cancer subtypes differ in morphologies, effector landscapes, and metabolic status with therapeutically tractable vulnerabilities.

    “Interestingly, besides the distinct morphologies and effector landscapes, the two subtypes also differ in metabolic status with therapeutically tractable vulnerabilities.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Yuan, 2018, Differential effector engagement by oncogenic KRAS, Cell Rep. source

      Not checked in the free run.

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    Premisecitation

    KP tumors had higher levels of somatic mutations, inflammatory and immune checkpoint markers, and prolonged relapse-free survival.

    “while higher levels of somatic mutations, inflammatory and immune checkpoint markers, and prolonged relapse-free survival were observed in KP tumors.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Skoulidis, 2015, Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities, Cancer Discov. source

      Not checked in the free run.

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    Premisecitation

    KRAS-mutant cancer cells dependent on or addicted to KRAS oncogene are more associated with an epithelial phenotype, whereas those independent of KRAS adopt a mesenchymal phenotype.

    “KRAS-mutant cancer cells dependent on or addicted to KRAS oncogene are more associated with an epithelial phenotype, whereas those independent of KRAS adopt a mesenchymal phenotype (18).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Singh, 2009, A gene expression signature associated with “K-Ras addiction” reveals regulators of EMT and tumor cell survival, Cancer Cell. source

      Not checked in the free run.

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

    Premisecitation

    Oncogenic KRAS can activate various downstream effector pathways, and the best characterized are PI3K and MAPK.

    “Oncogenic KRAS can activate various downstream effector pathways, and the best characterized are phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinases (MAPK) (23–25).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [23] McCormick, 2015, KRAS as a therapeutic target, Clin Cancer Res. source

      Not checked in the free run.

    • cites [24] Simanshu, 2017, RAS proteins and their regulators in human disease, Cell. source

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    • cites [25] Yuan, 2018, Differential effector engagement by oncogenic KRAS, Cell Rep. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ZEB1 suppression by miR-200 expression or mocetinostat re-sensitized mesenchymal cells to MEK inhibition and markedly reduced in vivo tumor growth.

    “ZEB1 suppression by miR-200 expression or histone deacetylase inhibitor (mocetinostat) re-sensitized mesenchymal cells to MEK inhibition and markedly reduced in vivo tumor growth.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Peng, 2019, ZEB1 suppression sensitizes KRAS mutant cancers to MEK inhibition by an IL17RD-dependent mechanism, Sci Transl Med. source

      Not checked in the free run.

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    Premisecitation

    Genomic alterations co-occurring with mutant KRAS stratify lung adenocarcinomas and define pathobiological properties and therapeutic vulnerabilities.

    “This work argued that genomic alterations co-occurring with mutant KRAS stratify lung adenocarcinomas and define pathobiological properties and therapeutic vulnerabilities.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Skoulidis, 2015, Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities, Cancer Discov. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation

    Chemotherapeutics used for combination treatment may need to be reconsidered in future studies, given that distinct amino acid substitutions of KRAS oncoproteins differed in their response to commonly used chemotherapy agents.

    “chemotherapeutics used for combination treatment may need to be reconsidered in future studies, given that distinct amino acid substitutions of KRAS oncoproteins differed in their response to the commonly-used chemotherapy agents (9, 11).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [9] Garassino, 2011, Different types of K-Ras mutations could affect drug sensitivity and tumour behaviour in non-small-cell lung cancer, Ann Oncol. source

      Not checked in the free run.

    • cites [11] Renaud, 2018, KRAS-specific amino acid substitutions are associated with different responses to chemotherapy in advanced non-small-cell lung cancer, Clin Lung Cancer. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Despite the rarity of HLA-C*08:02, this study demonstrated the promise of T-cell-based immunotherapy for targeting KRASG12D and HLA-C*08:02.

    “Despite the rarity of HLA-C*08:02, this study demonstrated the promise of T-cell–based immunotherapy for targeting KRASG12D and HLA-C*08:02.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Tran, 2016, T-cell transfer therapy targeting mutant KRAS in cancer, N Engl J Med. source

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  • May combine two claims.

    Interpretationreasoning

    Co-occurring alterations further increase heterogeneous complexity, which may explain inconsistent outcomes of clinical trials with KRAS-mutant lung cancers.

    “Apparently, co-occurring alterations further increase the heterogeneous complexity, which may explain inconsistent outcomes of clinical trials with KRAS-mutant lung cancers.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    MRTX849 shows broad-spectrum anti-tumor activity in a panel of patient- and cell-derived in vivo tumor models with KRAS G12C-substitution, with complete tumor regression observed in a subset of these models.

    “MRTX849 shows broad-spectrum anti-tumor activity in a panel of patient- and cell-derived in vivo tumor models with KRAS G12C-substitution, with complete tumor regression observed in a subset of these models.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Papadopoulos, 2019, A phase I/II multiple expansion cohort trial of MRTX849 in patients with advanced solid tumors with KRAS G12C mutation, J Clin Oncol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a phase I trial of AMG510 in 32 patients with KRASG12C mutation, five of 10 evaluable NSCLC patients had a partial response, four had stable disease, achieving a disease control rate of 90% (9/10).

    “Five of 10 evaluable patients with NSCLC had a partial response, and four had stable disease, in total achieving a disease control rate of 90% (9/10).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites NCT03600883

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    Premisecitation

    A subgroup analysis demonstrated that patients harboring G12V and G12C KRAS mutations appeared to experience higher response rate and longer PFS for the combination arm.

    “a subgroup analysis demonstrated that patients harboring G12V and G12C KRAS mutations appeared to experience higher RR and longer PFS for the combination arm”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Li, 2018, Assessing therapeutic efficacy of MEK inhibition in a KRAS(G12C)-driven mouse model of lung cancer, Clin Cancer Res. source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    The inconsistency between the phase II and phase III selumetinib plus docetaxel results was unclear, and possible mechanisms include genomic and phenotypic heterogeneity within recruited patients.

    “Whereas, the inconsistency with previous phase II trial results was unclear, a multitude of possible mechanisms, such as the aforementioned genomic (diverse point mutations and co-occurring alterations) and phenotypic (different EMT status) heterogeneity within the recruited patients, might be anticipated.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Chemotherapy plus immune checkpoint blockade has been recently approved as the first-line regimen for NSCLC, including patients with KRAS mutations.

    “chemotherapy plus immune checkpoint blockade has been recently approved as the first-line regimen for NSCLC, including patients with KRAS mutations (45, 46).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [45] Paz-Ares, 2018, Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer, N Engl J Med. source

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    • cites [46] Socinski, 2018, Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC, N Engl J Med. source

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  • May combine two claims.

    Interpretationreasoning

    Targeting the inactive, GDP-bound form of KRAS is a realistic and promising anti-RAS therapeutic.

    “targeting the inactive, GDP-bound form of KRAS is a realistic and promising anti-RAS therapeutic.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In a phase II trial, selumetinib plus docetaxel compared with docetaxel alone had median overall survival of 9.4 vs 5.2 months, not statistically significant (HR 0.80, 80% CI 0.56-1.14; one-sided p=0.21).

    “the primary endpoint of the study—median overall survival—was 9.4 months for the combination (selumetinib plus docetaxel) compared with 5.2 months for the control (placebo and docetaxel), although this difference was not statistically significant [hazard ratio (HR) for death 0·80, 80% CI 0·56–1·14; one-sided p = 0·21].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] Janne, 2013, Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study, Lancet Oncol. source

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    Premisecitation

    Despite AZD4785 being safe and well-tolerated, the first phase I trial failed, which might be due to targeting both mutant and wild-type KRAS mRNA for degradation.

    “Despite AZD4785 being safe and well-tolerated, the first phase I trial failed, which might be due to the fact that AZD4785 targets both mutant and wild-type KRAS mRNA for degradation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] Ross, 2017, Targeting KRAS-dependent tumors with AZD4785, a high-affinity therapeutic antisense oligonucleotide inhibitor of KRAS, Sci Transl Med. source

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    Premisecitation

    Lim et al. reported the synthesis of a GDP analog, SML-8-73-1, which covalently modifies cysteine 12 of KRasG12C and competes with GTP and GDP for active site binding in a cellular context.

    “Lim et al. reported the synthesis of a GDP analog, SML-8-73-1, which contains an electrophilic chloroacetamide attached to the β-phosphate. This analog can covalently modify cysteine 12 of KRasG12C and, as a result, it competes with GTP and GDP for active site binding in a cellular context (38).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Lim, 2014, Therapeutic targeting of oncogenic K-Ras by a covalent catalytic site inhibitor, Angew Chem Int Ed Engl. source

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    Premisecitation

    AMG510 treatment was well-tolerated, with primarily grade 1 events (68%); two grade 3 treatment-related adverse events (anemia and diarrhea) and no grade 4 or more severe treatment-related adverse effects were reported.

    “Importantly, the treatment was well-tolerated, with primarily grade 1 events (68%). Two grade 3 treatment-related AEs were reported (anemia and diarrhea). No grade 4 or more severe treatment-related adverse effects were reported.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites NCT03600883

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  • Classified as probably not a substantial claim.

    Premisecitation

    The previous perception that mutant KRAS was persistently locked in its active GTP-bound state might not be true.

    “This work also suggested that the previous perception of mutant KRAS was persistently locked in its active GTP-bound state might not be true.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Ostrem, 2013, K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions, Nature. source

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    Premisecitation

    Trametinib plus docetaxel had a response rate of 33% and median survival of 11.1 months in patients with recurrent KRAS-mutant NSCLC.

    “Trametinib plus docetaxel had a RR of 33% and median survival of 11.1 months in patients with recurrent KRAS-mutant NSCLC.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [50] Gadgeel, 2019, S1507: phase II study of docetaxel and trametinib in patients with G12C or non-G12C KRAS mutation positive (+) recurrent non-small cell lung cancer (NSCLC), J Clin Oncol. source

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    Premisecitation

    ARS853 selectively reduced KRAS-GTP levels by more than 90% and increased the in vitro hydrolytic reaction rate by 600-fold compared to the initial compound used in Ostrem et al.

    “ARS853 was developed (40), which selectively reduced KRAS-GTP levels by more than 90% and increased the in vitro hydrolytic reaction rate by 600-fold compared to the initial compound used in Ostrem et al. (37).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [40] Patricelli, 2016, Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state, Cancer Discov. source

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    • cites [37] Ostrem, 2013, K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions, Nature. source

      Not checked in the free run.

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    Premisecitation

    SHP2 is a non-receptor protein tyrosine phosphatase encoded by PTPN11, ubiquitously expressed, involved in signal transduction downstream of multiple growth factors, cytokine, and integrin receptors, and functions as an essential player in oncogenesis.

    “SHP2 is a non-receptor protein tyrosine phosphatase, encoded by the PTPN11 gene that is ubiquitously expressed. SHP2 is involved in signal transduction downstream of multiple growth factors, cytokine, and integrin receptors and, not surprisingly, functions as an essential player in oncogenesis (51, 52).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [51] Chan, 2007, PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase, Blood. source

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    • cites [52] Matozaki, 2009, Protein tyrosine phosphatase SHP-2: a proto-oncogene product that promotes Ras activation, Cancer Sci. source

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    Premisecitation

    Neratinib almost completely suppressed the emergence of tumors, whereas erlotinib failed to reproduce the same effect.

    “Neratinib, a multi-ERBB inhibitor (70, 71), almost completely suppressed the emergence of tumors. In sharp contrast, erlotinib failed to reproduce the same effect.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] Kruspig, 2018, The ERBB network facilitates KRAS-driven lung tumorigenesis, Sci Transl Med. source

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    Premisecitation

    Both studies revealed a requirement for simultaneous inhibition of multiple ERBB while targeting a single member of the family was not effective.

    “Notably, both studies revealed a requirement for simultaneous inhibition of multiple ERBB while targeting a single member of the family was not effective.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [61] Kruspig, 2018, The ERBB network facilitates KRAS-driven lung tumorigenesis, Sci Transl Med. source

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    • cites [62] Moll, 2018, Afatinib restrains K-RAS-driven lung tumorigenesis, Sci Transl Med. source

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  • May combine two claims.

    Premisecitation

    Recent studies demonstrated that activation of ERBB signaling was required for KRASG12D-driven lung tumorigenesis in preclinical mouse models and that pan-ERBB inhibition other than EGFR inhibition alone was strikingly effective to inhibit KRAS-mutant tumor growth and progression.

    “recent studies have challenged this paradigm, which instead demonstrated that the activation of ERBB signaling was required for KRASG12D-driven lung tumorigenesis in preclinical mice models and that pan-ERBB inhibition other than EGFR inhibition alone was strikingly effective to inhibit KRAS-mutant tumor growth and progression (61, 62).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [61] Kruspig, 2018, The ERBB network facilitates KRAS-driven lung tumorigenesis, Sci Transl Med. source

      Not checked in the free run.

    • cites [62] Moll, 2018, Afatinib restrains K-RAS-driven lung tumorigenesis, Sci Transl Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    EGFR inhibition initiated a rapid resistance mechanism involving non-EGFR ERBB family members, which triggered a tumor escape mechanism.

    “EGFR inhibition initiated a rapid resistance mechanism involving non-EGFR ERBB family members, which triggered a tumor escape mechanism.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [62] Moll, 2018, Afatinib restrains K-RAS-driven lung tumorigenesis, Sci Transl Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SHP2 is necessary for various contexts upon MEK blockade and is required to re-establish MAPK signaling.

    “SHP2, the key integrator of RTK-RAS signaling, was necessary for various contexts upon MEK blockade and required to re-establish MAPK signaling.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [54] Mainardi, 2018, SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo, Nat Med. source

      Not checked in the free run.

    • cites [55] Ruess, 2018, Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase, Nat Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Genetic mouse models revealed that EGFR deletion attenuates mutant KRAS activity and transiently reduces tumor growth.

    “Genetic mouse models revealed that EGFR deletion attenuates mutant KRAS activity and transiently reduces tumor growth.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [62] Moll, 2018, Afatinib restrains K-RAS-driven lung tumorigenesis, Sci Transl Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Afatinib blocked compensatory ERBB2 and ERBB3 activation, whereas erlotinib and gefitinib did not.

    “afatinib blocked compensatory ERBB2 and ERBB3 activation, whereas erlotinib and gefitinib did not.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [62] Moll, 2018, Afatinib restrains K-RAS-driven lung tumorigenesis, Sci Transl Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Clinical trials confirmed that patients with KRAS-mutant cancers generally have a poor response to first-generation EGFR inhibitors erlotinib and gefitinib, and the presence of KRAS mutations is used as a biomarker to exclude patients for EGFR inhibitor therapy.

    “clinical trials confirmed that patients with KRAS-mutant cancers generally have a poor response to the first generation of EGFR inhibitors, such as erlotinib and gefitinib, and the presence of KRAS mutations is used as a biomarker to exclude patients for EGFR inhibitor therapy (7, 8, 69).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [7] Rulli, 2015, Value of KRAS as prognostic or predictive marker in NSCLC: results from the TAILOR trial, Ann Oncol. source

      Not checked in the free run.

    • cites [8] Papadimitrakopoulou, 2016, The BATTLE-2 study: a biomarker-integrated targeted therapy study in previously treated patients with advanced non-small-cell lung cancer, J Clin Oncol. source

      Not checked in the free run.

    • cites [69] Cadranel, 2012, Impact of systematic EGFR and KRAS mutation evaluation on progression-free survival and overall survival in patients with advanced non-small-cell lung cancer treated by erlotinib in a French prospective cohort (ERMETIC project–part 2), J Thorac Oncol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Targeting C-Raf rather than B-Raf kinase could recapitulate the effect of Kras ablation and effectively inhibit tumor development without inducing significant toxicities in mouse models of Kras/Trp53-mutant lung adenocarcinoma.

    “Targeting of C-Raf rather than of B-Raf kinase could recapitulate the effect of Kras ablation and effectively inhibit tumor development without inducing significant toxicities in mouse models of Kras/Trp53-mutant lung adenocarcinoma.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [74] Blasco, 2011, c-Raf, but not B-Raf, is essential for development of K-Ras oncogene-driven non-small cell lung carcinoma, Cancer Cell. source

      Not checked in the free run.

    • cites [75] Karreth, 2011, C-Raf is required for the initiation of lung cancer by K-Ras(G12D), Cancer Discov. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In human cancer cell lines or tumors bearing KRAS mutations, high levels of basal autophagy were observed, making inhibition of autophagy therapeutically actionable in KRAS-driven tumors.

    “in human cancer cell lines or tumors bearing KRAS mutations, high levels of basal autophagy were observed, making inhibition of autophagy therapeutically actionable in KRAS-driven tumors (64, 65).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [64] Guo, 2011, Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis, Genes Dev. source

      Not checked in the free run.

    • cites [65] Eng, 2016, Macroautophagy is dispensable for growth of KRAS mutant tumors and chloroquine efficacy, Proc Natl Acad Sci USA. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ablation of C-Raf did not affect Mek or Erk phosphorylation, suggesting that C-Raf-mediated Kras signaling is independent of the MAPK cascade.

    “ablation of C-Raf did not affect Mek or Erk phosphorylation, suggesting that C-Raf-mediated Kras signaling is independent of the MAPK cascade.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [76] Sanclemente, 2018, c-RAF ablation induces regression of advanced Kras/Trp53 mutant lung adenocarcinomas by a mechanism independent of MAPK signaling, Cancer Cell. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Targeting MEK alone is frequently hampered by adaptive resistance, which is complex and context-dependent, and can involve activation of various RTKs, including ERBB family, AXL, PDGFR-α, or FGFR1.

    “targeting of MEK alone is frequently hampered by adaptive resistance, which is complex and context-dependent, and can involve activation of various RTKs, including ERBB family, AXL, PDGFR-α, or FGFR1 (26, 53, 59–62).”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [26] 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

      Not checked in the free run.

    • cites [53] Caunt, 2015, MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road, Nat Rev Cancer. source

      Not checked in the free run.

    • cites [59] Sun, 2014, Intrinsic resistance to MEK inhibition in KRAS mutant lung and colon cancer through transcriptional induction of ERBB3, Cell Rep. source

      Not checked in the free run.

    • cites [60] Boshuizen, 2018, Cooperative targeting of melanoma heterogeneity with an AXL antibody-drug conjugate and BRAF/MEK inhibitors, Nat Med. source

      Not checked in the free run.

    • cites [61] Kruspig, 2018, The ERBB network facilitates KRAS-driven lung tumorigenesis, Sci Transl Med. source

      Not checked in the free run.

    • cites [62] Moll, 2018, Afatinib restrains K-RAS-driven lung tumorigenesis, Sci Transl Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Kinsey et al. initiated off-label treatment for a patient with metastatic PDAC with trametinib and hydroxychloroquine and observed a striking disease response with a 50% reduction in tumor burden without toxicity.

    “Kinsey et al. initiated off-label treatment for a patient with metastatic PDAC with trametinib and hydroxychloroquine, both of which have been clinically approved for other indications. They observed a striking disease response with a 50% reduction in tumor burden without toxicity (67).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Kinsey, 2019, Protective autophagy elicited by RAF–>MEK–>ERK inhibition suggests a treatment strategy for RAS-driven cancers, Nat Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Elimination of C-Raf did not induce systemic toxicity, in contrast to MEK inhibitors.

    “This might explain, to some extent, why the elimination of C-Raf did not induce systemic toxicity, in contrast to MEK inhibitors.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [76] Sanclemente, 2018, c-RAF ablation induces regression of advanced Kras/Trp53 mutant lung adenocarcinomas by a mechanism independent of MAPK signaling, Cancer Cell. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    C-Raf ablation completely prevented Kras-driven NSCLC without inducing deleterious effects, whereas B-Raf ablation did not, indicating that B-Raf is dispensable for Kras oncogenic signaling.

    “C-Raf ablation completely prevented Kras-driven NSCLC without inducing deleterious effects, which, however, was not the case with B-Raf ablation, indicating that B-Raf is dispensable for Kras oncogenic signaling.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [76] Sanclemente, 2018, c-RAF ablation induces regression of advanced Kras/Trp53 mutant lung adenocarcinomas by a mechanism independent of MAPK signaling, Cancer Cell. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Co-occurring genetic mutations can lead to differential downstream effectors engaged by mutant KRAS and have been reported to significantly affect tumor immune signatures and responses to immunotherapy.

    “Co-occurring genetic mutations, which can lead to differential downstream effectors engaged by mutant KRAS, have been reported to significantly affect the tumor immune signatures (25, 29, 31, 35) and responses to immunotherapy (30).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [25] Yuan, 2018, Differential effector engagement by oncogenic KRAS, Cell Rep. source

      Not checked in the free run.

    • cites [29] Skoulidis, 2015, Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities, Cancer Discov. source

      Not checked in the free run.

    • cites [31] Kitajima, 2019, Suppression of STING associated with LKB1 loss in KRAS-driven lung cancer, Cancer Discov. source

      Not checked in the free run.

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

    Premisecitation

    Considerably convincing evidence has shown the importance of immune checkpoint blockade for treating various cancers.

    “Considerably convincing evidence has shown the importance of immune checkpoint blockade for treating various cancers (87).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [87] Postow, 2015, Immune checkpoint blockade in cancer therapy, J Clin Oncol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pembrolizumab was superior to chemotherapy in advanced NSCLC (potentially including patients with KRAS mutations), among which more than 50% had high PD-L1 expression.

    “A landmark trial (KEYNOTE-024) demonstrated that pembrolizumab was superior to chemotherapy in advanced NSCLC (potentially including patients with KRAS-mutations), among which more than 50% had high PD-L1 expression (95).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [95] Reck, 2016, Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer, N Engl J Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pembrolizumab in combination with chemotherapy is approved for metastatic, non-squamous NSCLC and for squamous lung carcinoma excluding EGFR or ALK mutations.

    “The promising results from these studies have led to the approval of pembrolizumab in combination with chemotherapy (carboplatin-pemetrexed) for metastatic, non-squamous NSCLC, and the approval of pembrolizumab in combination with chemotherapy (carboplatin and Taxol) for patients with squamous lung carcinoma, excluding those carrying EGFR or ALK mutations.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [45] Paz-Ares, 2018, Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer, N Engl J Med. source

      Not checked in the free run.

    • cites [97] Gandhi, 2018, Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer, N Engl J Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A majority of preclinical studies using immune-competent mouse models relied on mouse models with a single genetic background, which limits the power to assess the potential influence of other co-occurring mutations such as STK11 alterations.

    “Although, preclinical studies using immune-competent mouse models verified the promising efficacy of checkpoint blockade in the Kras-mutant setting (92, 102, 103), a majority of these studies relied on mouse models with a single genetic background, which limits the power to assess the potential influence of other co-occurring mutations (e.g., STK11 alterations).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [92] Dong, 2017, Potential predictive value of TP53 and KRAS mutation status for response to PD-1 blockade immunotherapy in lung adenocarcinoma, Clin Cancer Res. source

      Not checked in the free run.

    • cites [102] Choi, 2019, Pulsatile MEK inhibition improves anti-tumor immunity and T cell function in murine Kras mutant lung cancer, Cell Rep. source

      Not checked in the free run.

    • cites [103] Lee, 2019, The combination of MEK inhibitor with immunomodulatory antibodies targeting programmed death 1 and programmed death ligand 1 results in prolonged survival in Kras/p53-driven lung cancer, J Thorac Oncol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acquisition of resistance enables KRAS-mutant lung cancer cells to bypass canonical KRAS effectors but entails hyperactive AXL/eIF4E, increased protein turnover in the ER, and adaptive activation of an ER stress-relief unfolded protein response survival pathway maintained by HSP90.

    “Mechanistically, acquisition of resistance enables KRAS-mutant lung cancer cells to bypass canonical KRAS effectors but entail hyperactive AXL/eIF4E, increased protein turnover in the endoplasmic reticulum (ER), and adaptive activation of an ER stress-relief unfolded protein response survival pathway whose integrity is maintained by HSP90.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86] Yang, 2019, HSP90/AXL/eIF4E-regulated unfolded protein response as an acquired vulnerability in drug-resistant KRAS-mutant lung cancer, Oncogenesis. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MAST1 expression is increased in cisplatin-resistant cells and functions as a MAP3K, thereby activating MEK1.

    “The mechanistic study showed that MAST1 expression was increased in resistant cells and functioned as a MAP3K (MAPK kinase kinase), thereby activating MEK1 in cisplatin-resistant cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85] Jin, 2018, MAST1 drives cisplatin resistance in human cancers by rewiring cRaf-independent MEK activation, Cancer Cell. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pemetrexed-resistant KRAS-mutant lung cancer cells assume a mesenchymal phenotype and cross-resist MEK inhibitors.

    “In a recent study (86), we reported that pemetrexed-resistant KRAS-mutant lung cancer cells assume a mesenchymal phenotype and cross-resist MEK inhibitors.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86] Yang, 2019, HSP90/AXL/eIF4E-regulated unfolded protein response as an acquired vulnerability in drug-resistant KRAS-mutant lung cancer, Oncogenesis. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Conventional approaches such as combined chemotherapy and mTOR inhibitors, and combined cisplatin and MAST1 inhibitors, are encouraging but require further investigation in patients.

    “Conventional approaches, such as combined chemotherapy and mTOR inhibitors, as well as combined cisplatin and MAST1 inhibitors, are also encouraging but require further investigations in patients.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    New treatment strategies based on a deeper understanding of oncogenic KRAS pathobiology, such as abolishing C-RAF, blocking SHP2 rewiring, and inhibiting protective autophagy in response to MEK inhibitors, are highly promising with preliminary success in human patients.

    “New treatment strategies based on a deeper understanding of the pathobiology of oncogenic KRAS, such as abolishing C-RAF, blocking the universal rewiring of SHP2, and the protective autophagy in response to MEK inhibitors are highly promising with preliminary success in human patients.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: A striking response has been achieved with AMG510 in patients with KRASG12C.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Treating KRAS-mutant lung cancer remains a significant challenge, implying that the problem might be mechanism-related rather than the efficacy of targeting itself.

    “Given the presence of a variety of potent and specific chemicals, treating KRAS-mutant lung cancer remains a significant challenge, implying that the problem might be mechanism-related rather than the efficacy of targeting itself.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    A critical point is a high heterogeneity within KRAS-mutant tumors.

    “A critical point is a high heterogeneity within KRAS-mutant tumors.”
    Quote in the paperNot a substantial claim
60 of 60

  • The paper relies on this without support.

    There remains no clinically approved targeted therapy for KRAS-mutant NSCLC.

    “there remains no clinically approved targeted therapies”

  • The paper relies on this without support.

    Carcinogenic KRAS mutations lock the oncoprotein in a constitutively active state by activating downstream signaling cascades, leading to uncontrolled cell proliferation and survival.

    “Carcinogenic mutations impair the ability of KRAS to hydrolyze GTP and are thought to lock the oncoprotein in a constitutively active state by activating KRAS downstream signaling cascades, leading to uncontrolled cell proliferation and survival.”

  • The paper relies on this without support.

    Hyperactivation of the MAPK pathway is a key feature in KRAS-driven lung cancer cells.

    “hyperactivation of the mitogen-activated protein kinase (MAPK) pathway is generally recognized as a key feature in KRAS-driven lung cancer cells.”

  • The paper relies on this without support.

    The G12C substitution is the most common subtype in KRAS-mutant lung cancer and shows more prominent engagement with MAPK signaling.

    “the G12C substitution (44%), the most common subtype in KRAS-mutant lung cancer, shows more prominent engagement with MAPK signaling.”

  • The paper relies on this without support.

    Tumor cells depend on macroautophagy to cope with oncogene-induced metabolic stress.

    “Tumor cells depend on macroautophagy to cope with oncogene-induced metabolic stress.”

  • The paper relies on this without support.

    Platinum-based chemotherapy is still widely used for patients with KRAS-mutant lung cancer.

    “Currently, the platinum-based chemotherapy is still widely used for patients with KRAS-mutant lung cancer.”

  • The paper relies on this without support.

    The efficacy of chemotherapy in KRAS-mutant lung cancer is very limited, and durable response is generally short.

    “However, the efficacy of chemotherapy is very limited, and durable response is generally short.”

  • The paper relies on this without support.

    Blocking RAS-mediated PI3K activation inhibits the progression of KRAS-driven tumors.

    “Blocking RAS-mediated PI3K activation has also shown to inhibit the progression of KRAS-driven tumors.”

  • The paper relies on this without support.

    The therapeutic efficacy of immune checkpoint blockade varies individually due to high tumor heterogeneity and lack of reliable biomarkers to stratify patients.

    “However, the therapeutic efficacy varies individually due to the high heterogeneity of tumors and the lack of reliable biomarkers to stratify the patients.”

  • The paper relies on this without support.

    A striking response has been achieved with AMG510 in patients with KRASG12C.

    “A striking response has been achieved with AMG510 in patients with KRASG12C.”

  • The paper relies on this without support.

    The great success of immunotherapy has been witnessed in the treatment of patients with various tumors.

    “The great success of immunotherapy has been witnessed in the treatment of patients with various tumors, but more evidence is required in cancer patients with KRAS mutations.”
11 of 11

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?

  • KRASG12C mutation is present in approximately 15% of lung adenocarcinoma and 0%-8% of other cancers.

    “which is present in ~15% of lung adenocarcinoma and 0%–8% of other cancers (Table 1).8,9”

    From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [9]

  • STK11, TP53 or CDKN2A/CDKN2B co-mutations are frequent in KRAS-mutant tumours, and KRAS-STK11 or KRAS-KEAP1 co-mutation patterns are associated with treatment resistance in preclinical models and poor outcomes in NSCLC patients receiving immune-checkpoint inhibitors with or without chemotherapy.

    “co-mutations in the tumour-suppressor genes STK11, TP53 or CDKN2A/CDKN2B are frequently found in KRAS-mutant tumours35. Patients in the KRAS–STK11 co-mutation group can be subdivided into KEAP1-wild-type or KEAP1-mutant subgroups, and KEAP1 can also be co-mutated with KRAS in the absence of STK11 mutations; each of these co-mutation patterns is associated with resistance to treatment in”

    From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [35]

Self-check

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

  • AMG510 trial patient counts total 35, not 32

    Minor

    The listed cancer-type counts sum to 35 patients, not 32. The later disposition counts also total 35 (26 still under study and nine discontinued).

    Reported 32 · recomputed 35

1 of 1

Cites

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Sorted by citations

Authors
Yang, H., Liang, S.-Q., Schmid, R. A., & Peng, R.-W.
Affiliations
University of Bern (CH)
Corresponding author
Peng, Ren-Wang
ORCID
Venue
Frontiers in Oncology
Publisher
Frontiers Media SA
Published
2019-09-25
Volume
9
Pages
953-953
ISSN
2234-943X (ISSN-L)
DOI
10.3389/fonc.2019.00953
PMC
PMC6773824
OpenAlex
W2976596814
Cited by
129
References
103
Citations by year
2026: 1 · 2025: 11 · 2024: 13 · 2023: 17 · 2022: 24 · 2021: 34 · 2020: 24 · 2019: 3 · 2018: 1
FWCI
3.62
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Oncology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • BORIS (University Library Bern) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Open Access CRIS of the University of Bern
Funders
China Scholarship Council
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
Keywords
KRAS mutation, non-small cell lung cancer, tumor heterogeneity, epithelial-mesenchymal transition, precision medicine, targeted therapy

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.

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