CoChat
Sign Up
Cited by 360Pancreatic and Hepatic Oncology ResearchProtein Kinase Regulation and GTPase SignalingPancreatitis Pathology and Treatment

KRAS mutation in pancreatic cancer

Open access
Luo, Ji·2021·Seminars in Oncology
DOI 10.1053/j.seminoncol.2021.02.003PMC PMC8380752
Open this paper in CoChat — free account

Abstract

Pancreatic cancer is a recalcitrant cancer with one of the lowest 5-year survival rates. A hallmark of pancreatic cancer is the prevalence of oncogenic mutation in the KRAS gene. The KRAS oncogene plays a critical role in the initiation and maintenance of pancreatic tumors and its signaling network represents a major target for therapeutic intervention. A number of inhibitors have been developed against kinase effectors in various Ras signaling pathways. Their clinical activity, however, has been disappointing thus far. More recently, covalent inhibitors targeting the KRASG12C oncoprotein have been developed. These inhibitors showed promising activity in KRASG12C mutant pancreatic cancer in early clinical trials. This review will present an updated summary of our understanding of mutant KRAS function in pancreatic cancer and discuss therapeutic strategies that target oncogenic KRAS signaling in this disease.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes how mutant KRAS drives pancreatic ductal adenocarcinoma and why targeting it has been difficult, while highlighting recent KRASG12C covalent inhibitors as a therapeutic breakthrough. It also outlines combination strategies needed for non-G12C KRAS pancreatic cancers.

Key findings

  • KRAS mutation was found in 85.8% (665/775) of pancreatic cancer samples analyzed through cBioPortal from four large studies; among KRAS mutations, G12D was 39.2%, G12V 32.5%, G12R 17%, and G12C only 1.7%.
  • KRAS mutation appears early in pancreatic intraepithelial neoplasia, detected in 25% of PanIN-1A and 38% of PanIN-1B; progression to invasive disease is linked with additional mutations in CDKN2A, TP53, and SMAD4.
  • In a phase II sotorasib trial, among 12 patients with KRASG12C pancreatic cancer, 1 had a partial response, 8 had stable disease, and 2 had progressive disease; a single PDAC patient treated with MRTX849 was reported in abstract form to have a partial response.
  • Single-agent inhibitors of MAPK, PI3K, or mTOR pathways showed poor clinical efficacy in pancreatic cancer, leading the review to argue that combination therapy will be necessary, including strategies targeting autophagy or immune checkpoints.

Methods

  • Narrative review synthesizing basic, preclinical, and clinical literature on KRAS biology, pancreatic cancer models, and KRAS-directed therapies.
  • Mutation frequency and codon bias were examined using cBioPortal data from four large-scale pancreatic cancer studies, covering 775 tumor samples.
  • Evidence also draws on human cell lines, genetically engineered mouse models, organoids, and early-phase clinical trial reports; no new primary experimental data are presented.

Limitations

  • The paper states that KRAS mutation’s prognostic value in PDAC remains mixed, with conflicting findings across localized, locally advanced, and metastatic settings, and calls for larger cohorts with more homogeneous clinical and tumor profiles.
  • The paper notes that reasons for tissue-specific KRAS codon bias and stage-specific KRAS functions are unclear.
  • Evident from the text: clinical data for KRASG12C inhibitors in pancreatic cancer are very limited (12 patients in one phase II trial and one case report for another agent), and as a narrative review it does not use a systematic search or quantitative meta-analysis.

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

Integrity signals

Registry

Crossref · 10.1053/j.seminoncol.2021.02.003

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 117 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Most KRAS mutations in PDAC are missense mutations at the hotspot residues G12, G13, and Q61.

    “Most are missense mutations that occur in the three hotspot residues G12, G13 and Q61 (Figure 3).”
    Quote in the paperNot a substantial claim
  • Findingcitation

    KRAS mutation occurs in about 85% of pancreatic ductal adenocarcinomas.

    “Amongst these are four canonical mutations – KRAS (~85%), TP53 (60–70%), CDKN2A (>50%), and SMAD4 (~50%).”
    • Also stated in: § KRAS mutation in the context of pancreatic cancer · hedged
      “An analysis of the cBioPortal database (48, 49) using four large scale pancreatic cancer studies (50–53) indicated that KRAS mutation occurs in 85.8% (665/775) of tumor samples.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [50] Biankin, 2012, Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes, Nature source

      Not checked in the free run.

    • cites [51] Bailey, 2016, Genomic analyses identify molecular subtypes of pancreatic cancer, Nature source

      Not checked in the free run.

    • cites [52] Witkiewicz, 2015, Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets, Nat Commun source

      Not checked in the free run.

    • cites [53] Sanchez-Vega, 2018, Oncogenic signaling pathways in the cancer genome atlas, Cell source

      Not checked in the free run.

    • Rests on an assumption: The four large-scale pancreatic cancer studies analyzed through cBioPortal are representative of PDAC generally.
    • Rests on an assumption: The cBioPortal mutation calls and sample set accurately reflect KRAS mutation status and codon distribution in PDAC.
  • Findingown data

    KRASG12C occurs in only 1.7% of KRAS-mutant PDACs.

    “The KRASG12C mutant allele, whose protein product is inhibitable with the recently developed KRASG12C covalent inhibitors, occurs only in 1.7% of KRAS mutant PDACs.”
    Quote in the paperNot a substantial claim
  • Findingown data

    KRASG12R occurs at high frequency in PDAC, about 17% of KRAS mutations.

    “As mentioned, the G12R mutation also occurs at high frequency in PDAC (17% of all KRAS mutations).”
    Quote in the paperNot a substantial claim
  • Interpretationreasoning

    KRAS mutation is likely an early and initiating event in human pancreatic cancer.

    “These findings indicate that KRAS mutation is likely an early and initiating event in human pancreatic cancer.”
    Quote in the paperSubstantial claim
  • May combine two claims. 35
  • Classified as probably not a substantial claim. 15

  • May combine two claims.

    Findingown data

    KRASG12D and KRASG12V are the most common KRAS mutations in PDAC, accounting for 39.2% and 32.5% of KRAS mutations, respectively.

    “KRASG12D and KRASG12V are most prevalent, at 39.2 and 32.5% of all KRAS mutations, respectively.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    These mutations shift Ras equilibrium to the GTP-bound state and uncouple Ras from upstream receptor inputs, driving constitutive signaling to downstream effectors.

    “These mutations dramatically shift the equilibrium of Ras protein to exist mostly in the GTP-bound state and effectively uncouple Ras proteins from upstream receptor inputs and drive constitutive signaling to downstream Ras effector pathways (13).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Simanshu, 2017, RAS proteins and their regulators in human disease, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In preclinical studies, KRASG12C inhibitors show significant selective in vitro toxicity in KRASG12C mutant cancer cells and inhibit growth of KRASG12C mutant xenograft and PDX tumors in mice.

    “In preclinical studies, KRASG12C inhibitors have demonstrated significant and selective in vitro toxicity in KRASG12C mutant cancer cells; and these inhibitors are effective at inhibiting the growth of KRASG12C mutant xenograft and PDX tumors in mice (21–23).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [21] Janes, 2018, Targeting KRAS mutant cancers with a Covalent G12C-specific inhibitor, Cell source

      Not checked in the free run.

    • cites [22] Canon, 2019, The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity, Nature source

      Not checked in the free run.

    • cites [23] Hallin, 2019, The KRASG12C Inhibitor, MRTX849, Provides Insight Toward Therapeutic Susceptibility of KRAS Mutant Cancers in Mouse Models and Patients, Cancer Discov source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The higher frequency of KRAS mutation in late-stage PDAC than in early PanIN suggests KRAS mutation may confer additional fitness benefits and be selected during progression.

    “The higher frequency of KRAS mutation observed in late-stage PDAC compared to early-stage PanIN suggests that KRAS mutation might confer additional fitness benefits, and thus be further selected, during tumor progression.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Mutations in the three Ras genes occur in over 10% of all human cancer.

    “Collectively, mutations in the three Ras genes occur in over 10% of all human cancer.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    The vast majority of Ras gene mutations are missense mutations at hotspots G12, G13, and Q61.

    “The vast majority of mutations in the Ras genes are mis-sense mutations at three hotspot residues G12, G13 and Q61.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The KRASG12R oncoprotein has distinct biochemical properties and is less effective at activating PI3K signaling and macropinocytosis.

    “although evidence suggests that the KRASG12R oncoprotein has distinct biochemical properties and is less effective at activating PI3K signaling and micropinocytosis (54).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Hobbs, 2020, Atypical KRAS(G12R) mutant is impaired in PI3K signaling and macropinocytosis in pancreatic cancer, Cancer Discov source

      Not checked in the free run.

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

    Premisecitation

    In colorectal cancer, KRAS mutation is a progression event that occurs after Wnt pathway mutation.

    “In contrast, in colorectal cancer KRAS mutation is a progression event that occurs after the initiation event of mutation in the Wnt pathway (57).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Markowitz, 2009, Molecular origins of cancer: molecular basis of colorectal cancer, N Engl J Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    KRAS mutation is more prevalent than HRAS and NRAS mutation in adenocarcinomas.

    “Currently, it is not fully understood why KRAS mutation is more prevalent than HRAS and NRAS mutation in adenocarcinomas.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Ras mutation is often a biomarker associated with poor prognosis and poor response to other targeted agents.

    “In addition, Ras mutation is often a biomarker associated with poor prognosis and poor response to other targeted agents.”
    Quote in the paperNot a substantial claim

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

    Premisereasoning

    Ras signals to multiple effector pathways whose activation favors oncogenic transformation, including MAPK, PI3K/AKT/mTOR, Rho/Rac/Ral, and phospholipase C.

    “These include the MAP-kinase (MAPK) pathway, the PI 3-kinase (PI3K)/AKT/mTOR pathway, the small GTPases Rho, Rac and Ral, and phospholipase C (Figure 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    KRASG12C inhibitors selectively react with the codon 12 cysteine on mutant KRASG12C and are far less reactive with cysteine residues on other proteins.

    “In this configuration, these compounds selectively react with the codon 12 cysteine on the mutant KRASG12C protein but are far less reactive towards cysteine residues on other proteins.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    KRAS mutation is found in about 85% of PDACs, 45% of colorectal adenocarcinomas, 30% of lung adenocarcinomas, and at lower frequencies in other tumor types.

    “KRAS mutation is found in ~85% of PDACs, ~45% of colorectal adenocarcinomas (CRC), ~30% of lung adenocarcinomas, and at lower frequencies in a wide array of tumor types (9).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Cox, 2014, Drugging the undruggable RAS: mission possible?, Nat Rev Drug Discov source

      Not checked in the free run.

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

    Premisecitation

    Hotspot mutations in Ras impair GAP binding (G12 and G13) or intrinsic GTPase activity (Q61).

    “The aforementioned hotspot mutations in Ras either impair GAP binding (G12 and G13 mutations) or the intrinsic GTPase activity (Q61 mutations) of Ras.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Hotspot mutations in Ras impair GTPase activity and lock Ras in its GTP-bound active state.

    “These mutations critically impair Ras GTPase activity and effectively lock the Ras protein in its GTP bound, active state.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    G12D and G12V are the most common KRAS mutations in PDAC, which also shows enrichment for G12R that is rarely found in colorectal and lung cancer.

    “G12D and G12V are the most common in PDAC, which also shows enrichment for the G12R mutation that is rarely found in CRC lung and lung cancer (16).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Haigis, 2017, The Devil Is in the Detail, Trends Cancer source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    KRAS mutation is detectable in 25% of PanIN-1A and 38% of PanIN-1B lesions.

    “KRAS mutation is readily detectable in 25% and 38% of PanIN-1A and PanIN-1B, respectively (55).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Lohr, 2005, Frequency of K-ras mutations in pancreatic intraductal neoplasias associated with pancreatic ductal adenocarcinoma and chronic pancreatitis: a meta-analysis, Neoplasia source

      Not checked in the free run.

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

    Premisereasoning

    G12C is prevalent in lung cancer, likely due to smoking-induced mutagenesis, but rare in PDAC and colorectal cancer.

    “Among the codon 12 mutations, the G12C mutation is prevalent in lung cancer (likely due to smoking-induced mutagenesis) but rare in PDAC and CRC (Figure 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    KRASG12C inhibitors extinguish oncogenic signaling from mutant KRASG12C but do not interfere with WT Ras or non-G12C mutant Ras proteins.

    “Consequently, these inhibitors effectively and specifically extinguish oncogenic signaling from mutant KRASG12C but do not interfere with the function of any WT Ras proteins or non-G12C mutant Ras proteins.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    EGFR inhibitor erlotinib in combination with gemcitabine gave a modest survival benefit compared to gemcitabine alone and was effectively abandoned after negative data for EGFR-directed therapy in KRAS-mutant colorectal cancer emerged.

    “The first approved, EGFR inhibitor erlotinib in combination with gemcitabine, gave a modest survival benefit compared to gemcitabine alone and was effectively abandoned by the community after negative data for EGFR-directed therapy in KRAS-mutant colorectal cancer emerged (6).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Moore, 2007, Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group, J Clin Oncol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PLK1 was identified as a synthetic lethal partner of mutant KRAS in colorectal cancer cells through a genome-wide RNAi screen, and PLK1 inhibition leads to more pronounced genomic instability in KRAS mutant cells.

    “We originally identified PLK1 as a synthetic lethal partner of mutant KRAS in colorectal cancer cells through a genome-wide RNAi screen and showed that PLK1 inhibition leads to more pronounced genomic instability in KRAS mutant cells (35).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Luo, 2009, A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene, Cell source

      Not checked in the free run.

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

    Premisecitation

    The PLK1 inhibitor onvansertib combined with chemotherapy and bevacizumab in KRAS mutant metastatic colorectal cancer in a phase II trial seems to demonstrate favorable tolerability and clinical response.

    “Recently, the PLK1 inhibitor onvansertib has been evaluated in combination with chemotherapy and bevacizumab in KRAS mutant metastatic colorectal cancer in a phase II trial, and this combination seems to demonstrate favorable tolerability and clinical response (36).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Ahn, 2020, Phase Ib/II study of the polo-like kinase 1 (PLK1) inhibitor, onvansertib, in combination with FOLFIRI and bevacizumab for second line treatment of KRAS-mutated metastatic colorectal cancer, Annals of Oncology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ERK phosphorylates CRAF to inhibit its activity, and the MAPK pathway induces DUSP phosphatases to dephosphorylate ERK and Sprouty and SPRED proteins to inhibit Ras activation.

    “For example, ERK can phosphorylate CRAF to inhibit its activity; MAPK pathway can induce the expression of DUSP phosphatases to dephosphorylate ERK and Sprouty and SPRED proteins to inhibit Ras activation (41).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Pratilas, 2010, Targeting the mitogen-activated protein kinase pathway: physiological feedback and drug response, Clin Cancer Res source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    NTRK-fusion occurs in only 0.5% of PDAC and the benefit of TRK inhibitors has not been systematically evaluated in PDAC beyond individual cases.

    “NTRK-fusion occurs in only 0.5% of PDAC and the benefit of TRK inhibitors have not been systematically evaluated in PDAC beyond individual cases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Inhibition of these stress-response pathways exacerbates oncogenic stress in KRAS mutant cells and impairs their viability.

    “Inhibition of these pathways therefore exacerbates oncogenic stress in KRAS mutant cells and impairs their viability (32, 33).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [32] Yu, 2013, Synthetic lethal genetic screens in Ras mutant cancers, Enzymes

      Not checked in the free run.

    • cites [33] Aguirre, 2018, Synthetic lethal vulnerabilities in KRAS-mutant cancers, Cold Spring Harb Perspect Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pancreatic cancer often harbors an immunosuppressive tumor microenvironment, making tumors refractory to immune checkpoint blockage using PD-1 and PD-L1 antibodies.

    “Pancreatic cancer often harbors an immunosuppressive tumor microenvironment (2). As a result, these tumors are refractory to immune checkpoint blockage using PD-1 and PD-L1 antibodies.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Ryan, 2014, Pancreatic adenocarcinoma, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Genome-wide RNAi and CRISPR screens have identified many synthetic lethal partners of KRAS, many of which are druggable.

    “A number of synthetic lethal genes have been identified using genome-wide RNAi and CRISPR screens, and many of these are druggable targets (32, 33).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [32] Yu, 2013, Synthetic lethal genetic screens in Ras mutant cancers, Enzymes

      Not checked in the free run.

    • cites [33] Aguirre, 2018, Synthetic lethal vulnerabilities in KRAS-mutant cancers, Cold Spring Harb Perspect Med source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Synthetic lethal interactions with KRAS tend to be context-dependent and reflect genetic heterogeneity of cancer cell lines, often observed only in a subset of KRAS mutant lines.

    “First, synthetic lethal interactions with KRAS tends to be context-dependent and they reflect the underlying genetic heterogeneity of cancer cell lines. A particular synthetic lethality interaction, therefore, is often observed only among a subset of KRAS mutant cancer cell lines.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Acute silencing of KRAS via RNAi or CRISPR in KRAS mutant pancreatic cancer cells results in cell cycle arrest, apoptosis, and suppression of anchorage-independent proliferation in vitro, and attenuated tumor growth and metastasis in xenograft models.

    “In KRAS mutant pancreatic cancer cells, acute silencing of KRAS via RNAi or CRISPR results in cell cycle arrest, apoptosis and suppression of anchorage-independent proliferation in vitro, and attenuated tumor growth and metastasis in xenograft models (66–68).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [66] Fleming, 2005, Molecular consequences of silencing mutant K-ras in pancreatic cancer cells: justification for K-ras-directed therapy, Mol Cancer Res source

      Not checked in the free run.

    • cites [67] Zorde Khvalevsky, 2013, Mutant KRAS is a druggable target for pancreatic cancer, Proc Natl Acad Sci U S A. source

      Not checked in the free run.

    • cites [68] Kamerkar, 2017, Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In late-stage PDAC with germline BRCA1 or BRCA2 mutation (~7.5% of patients), PARP inhibitor olaparib can extend progression-free survival but not overall survival.

    “Finally, in late-stage PDAC with germline mutation in BRCA1 or BRCA2 (~7.5% of the patients), the PARP inhibitor olaparib could extend progression free survival but not overall survival (8).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Golan, 2019, Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer, N Engl J Med source

      Not checked in the free run.

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

    Premisecitation

    TRK kinase inhibitors larotrectinib and entrectinib have been approved for solid tumors harboring an NTRK-fusion gene.

    “The TRK kinase inhibitors larotrectinib and entrectinib have been approved for solid tumors harboring a NTRK-fusion gene (7).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Drilon, 2018, Efficacy of Larotrectinib in TRK fusion-positive cancers in adults and children, N Engl J Med source

      Not checked in the free run.

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

    Premisenone given

    Current treatment of unresectable pancreatic cancer primarily relies on chemotherapies including gemcitabine and 5-FU.

    “Current treatment of unresectable pancreatic cancer primarily relies on chemotherapies including gemcitabine and 5-FU.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Cancer-associated fibroblasts in an activated tumor stroma may provide pro-survival paracrine signaling to cancer cells, reducing the cytotoxic effect of chemotherapeutic agents.

    “Cancer-associated fibroblasts in an activated tumor stroma may provide pro-survival paracrine signaling to cancer cells, thus reducing the cytotoxic effect of chemotherapeutic agents.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Pancreatic cancer often presents a dense, fibrotic tumor microenvironment with low blood vessel density, which hampers drug delivery to tumor cells.

    “Pancreatic cancer often presents a dense, fibrotic tumor microenvironment with low blood vessel density. This hampers drug delivery to tumor cells.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Non-G12C KRAS oncoproteins remain a therapeutic challenge.

    “Non-G12C KRAS oncoproteins remain a therapeutic challenge.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Normal and tumor organoid models have been developed from human and mouse pancreas.

    “Recently, normal and tumor organoid models have been developed from both human and mouse pancreas (82, 83).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [82] Boj, 2015, Organoid models of human and mouse ductal pancreatic cancer, Cell source

      Not checked in the free run.

    • cites [83] Tiriac, 2018, Organoid profiling identifies common responders to chemotherapy in pancreatic cancer, Cancer Discov source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In pancreatic cancer, KRAS dependency can be bypassed by elevated expression of transcription factor YAP1, which promotes EMT and confers cell-intrinsic resistance to KRAS loss.

    “In the context of pancreatic cancer, KRAS dependency can be by-passed by the elevated expression of the transcription factor YAP1, which promotes EMT and confers cell-intrinsic resistance to KRAS loss (84, 85).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [84] Shao, 2014, KRAS and YAP1 converge to regulate EMT and tumor survival, Cell source

      Not checked in the free run.

    • cites [85] Kapoor, 2014, Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer, Cell source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The MAPK pathway is critical for driving cell proliferation and survival in cells without KRAS mutation, whereas KRAS itself is not, likely due to redundant signaling from HRAS and NRAS.

    “This is not entirely surprising because the MAPK pathway is critical for driving cell proliferation and cell survival in cells without KRAS mutation, whereas KRAS itself is not (likely due to redundant signaling from HRAS and NRAS).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Acinar cells could serve as the cell of origin for PDAC and acinar-ductal metaplasia could occur during PanIN development.

    “Thus, acinar cells could also serve as the cell of origin for PDAC and acinar-ductal metaplasia could occur during PanIN development.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Mouse models of Kras-driven pancreatic cancer recapitulate human PDAC sufficiently to support conclusions about human disease.

  • May combine two claims.

    Premisecitation

    Preclinical findings suggest that inhibiting KRASG12C creates a pro-inflammatory tumor microenvironment and enhances tumor response to immune checkpoint inhibitors.

    “Preclinical data indicates that KRASG12C inhibition leads to a pro-inflammatory tumor microenvironment and potentiates tumor response to immune checkpoint inhibitors (22).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Canon, 2019, The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GEMMs combining Kras mutation with inactivation of Cdkn2a and Tp53, or with inactivation of TGFβ-SMAD4 signaling, develop invasive and metastatic PDAC, validating these tumor suppressor pathways in PDAC progression.

    “GEMMs with compound mutations that combine Kras mutation with the inactivation of tumor suppressor genes Cdkn2a and Tp53, or with the inactivation of the TGFβ-SMAD4 signaling pathway in the pancreas develop invasive and metastatic PDAC (74–76), thus validating the role of these tumor suppressor pathways in PDAC progression (4).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [74] Aguirre, 2003, Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma, Genes Dev source

      Not checked in the free run.

    • cites [75] Hingorani, 2005, Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice, Cancer Cell source

      Not checked in the free run.

    • cites [76] Ijichi, 2006, Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-beta signaling in cooperation with active Kras expression, Genes Dev source

      Not checked in the free run.

    • cites [4] Hruban, 2000, Genetic progression in the pancreatic ducts, Am J Pathol source

      Not checked in the free run.

    • Rests on an assumption: Mouse models of Kras-driven pancreatic cancer recapitulate human PDAC sufficiently to support conclusions about human disease.

  • May combine two claims.

    Premisecitation

    In that sotorasib trial, of the 12 patients with KRASG12C pancreatic cancer, one achieved partial response, eight had stable disease, and two had progressive disease.

    “Among these 12, 1 patient had a partial response, 8 patients had stable disease and 2 patients had progressive disease (24).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] Hong, 2020, KRAS(G12C) inhibition with Sotorasib in advanced solid tumors, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mouse PDAC tumors driven by mutant Kras experience metabolic alteration and are dependent on glucose and glutamine.

    “Mouse PDAC tumors driven by mutant Kras also experience metabolic alteration and are dependent on glucose and glutamine (73, 77).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [73] Ying, 2012, Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism, Cell source

      Not checked in the free run.

    • cites [77] Son, 2013, Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway, Nature source

      Not checked in the free run.

    • Rests on an assumption: Mouse models of Kras-driven pancreatic cancer recapitulate human PDAC sufficiently to support conclusions about human disease.

  • May combine two claims.

    Premisecitation

    Extinguishing mutant Kras expression in the pancreas led to rapid tumor regression, demonstrating a critical role of Kras in tumor maintenance.

    “Extinguishing the expression of mutant Kras in the pancreas led to rapid tumor regression, thus demonstrating a critical role of Kras in tumor maintenance (73, 78).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [73] Ying, 2012, Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism, Cell source

      Not checked in the free run.

    • cites [78] Collins, 2012, Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice, J Clin Invest source

      Not checked in the free run.

    • Rests on an assumption: Mouse models of Kras-driven pancreatic cancer recapitulate human PDAC sufficiently to support conclusions about human disease.

  • May combine two claims.

    Premisecitation

    A phase II trial in metastatic pancreatic cancer compared selumetinib plus MK-2206 with mFOLFOX chemotherapy; patients on the drug combination had slightly worse outcomes than controls.

    “In a phase II study combining the MEK inhibitor selumetinib with the AKT inhibitor MK-2206 in patients with metastatic pancreatic cancer, those receiving the drug combination actually did slightly worse than the control group receiving the mFOLFOX chemotherapy (94).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [94] Chung, 2017, Effect of Selumetinib and MK-2206 vs oxaliplatin and fluorouracil in patients with metastatic pancreatic cancer after prior therapy: SWOG S1115 study randomized clinical trial, JAMA Oncol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In that trial, a greater proportion of patients in the combination arm had grade 3 or higher toxicity and stopped treatment.

    “the combination arm had a higher fraction of patients that experienced grade 3 or higher toxicity and discontinued treatment (94).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [94] Chung, 2017, Effect of Selumetinib and MK-2206 vs oxaliplatin and fluorouracil in patients with metastatic pancreatic cancer after prior therapy: SWOG S1115 study randomized clinical trial, JAMA Oncol source

      Not checked in the free run.

46 of 46

  • The paper relies on this without support.

    The four large-scale pancreatic cancer studies analyzed through cBioPortal are representative of PDAC generally.

    “An analysis of the cBioPortal database (48, 49) using four large scale pancreatic cancer studies (50–53) indicated that KRAS mutation occurs in 85.8% (665/775) of tumor samples.”

  • The paper relies on this without support.

    The cBioPortal mutation calls and sample set accurately reflect KRAS mutation status and codon distribution in PDAC.

    “An analysis of the cBioPortal database (48, 49) using four large scale pancreatic cancer studies (50–53) indicated that KRAS mutation occurs in 85.8% (665/775) of tumor samples.”

  • The paper relies on this without support.

    Mouse models of Kras-driven pancreatic cancer recapitulate human PDAC sufficiently to support conclusions about human disease.

    “Genetically engineered mouse models (GEMMs) of Kras mutant pancreatic cancer have provided valuable insights on the molecular mechanism of this disease (71).”

  • The paper relies on this without support.

    Cancer cell line sensitivity to KRAS loss reflects tumor dependence in patients.

    “RNAi mediated gene knockdown studies and CRISPR mediated gene knockout studies in hundreds of cancer cell lines have shown that KRAS mutant pancreatic, lung and colorectal adenocarcinoma cells are more sensitive to the loss of the KRAS oncogene than KRAS WT cancer cell lines (64, 65) (Figure 4).”

  • The paper relies on this without support.

    KRAS mutations occur at a high frequency in pancreatic cancer.

    “due to the high prevalence of KRAS mutation in this disease.”

  • The paper relies on this without support.

    Thirty-nine percent of pancreatic ductal adenocarcinoma patients carry the KRASG12D mutation.

    “This will be very important for the 39% of patients with KRASG12D-mutated PDAC.”

  • The paper relies on this without support.

    Downstream of KRAS, the MAPK pathway is central to promoting cell proliferation and survival.

    “given this pathway’s central role in driving cell proliferation and cell survival downstream of KRAS.”
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 G12D is the most frequently mutated oncogenic KRAS subtype.

    “KRAS G12D is the most frequently mutated oncogenic KRAS subtype. 35-37”

    From Anti-tumor efficacy of HRS-4642 and its potential combination with proteasome inhibition in KRAS G12D-mutant cancer (2024) · cites this paper as [37]

    The section ‘Frequency and codon bias of KRAS mutations in pancreatic cancer’ reports that G12D is the most prevalent KRAS mutation in the pancreatic cancer samples analyzed (39.2%, versus 32.5% for G12V). The claim does not limit itself to pancreatic cancer, and the paper describes tissue-specific differences rather than establishing that G12D is the most frequent subtype across cancers. Page numbers were not supplied. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • KRAS G12C is present in only about 1%-2% of PDAC cases, limiting the relevance of KRAS G12C inhibitors in PDAC.

    “their relevance in pancreatic ductal adenocarcinoma remains limited because KRAS G12C is present in only about 1%–2% of PDAC cases (Luo, 2021).”

    From The antitumoral effect of statins in pancreatic ductal adenocarcinoma: a scoping review (2026) · cites this paper as Luo, 2021

  • In pancreatic cancers, KRAS G12D and G12V are the predominant mutations, at 40% and 32% of all KRAS mutations, respectively, while G12R accounts for nearly 17%.

    “In pancreatic cancers, KRAS G12D and G12V are the predominant mutations, at 40% and 32% of all KRAS mutations, respectively, while G12R mutation accounts for nearly 17% of all KRAS mutations in pancreatic cancer [50].”

    From Drugging KRAS: Current perspectives and state-of-art review (2022) · cites this paper as [50]

The citation lists haven’t been fetched yet

References 102 · Cited by 360

Research works printed but not linked: 1

  1. Markowitz, 2009, Molecular origins of cancer: molecular basis of colorectal cancer, N Engl J Med, 361, 2449, 10.1056/NEJMra0804588 · DOI · Paper page

Authors
Luo, J.
Affiliations
National Cancer Institute (US)
Corresponding author
Luo, Ji
ORCID
Luo, Ji
Venue
Seminars in Oncology
Publisher
Elsevier BV
Published
2021-02
Volume
48
Issue
1
Pages
10-18
ISSN
0093-7754 (ISSN-L)
DOI
10.1053/j.seminoncol.2021.02.003
PMC
PMC8380752
OpenAlex
W3132199378
Semantic Scholar
026d5b8acdb1b14d4b36fa3d262d01c6482a5db6
Cited by
360
References
102
Citations by year
2026: 56 · 2025: 106 · 2024: 102 · 2023: 66 · 2022: 26 · 2021: 4
FWCI
6.02
Type
journal article
Language
en
Open access
Licence
Locations
  • Seminars in Oncology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Cancer Institute (ZIA BC 011732)
  • National Institutes of Health
Topics
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
Keywords
KRAS mutation, pancreatic cancer, KRAS G12C, KRAS inhibitors, covalent KRAS inhibitor, Ras signaling, KRAS-targeted therapy
MeSH terms
Humans, Mutation, Pancreatic Neoplasms, Signal Transduction, 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.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review