Bracing for the storm: emerging resistance mechanisms to KRAS inhibitors in pancreatic cancer and strategies to overcome them

Abstract

Oncogenic KRAS mutations are a defining feature of pancreatic ductal adenocarcinoma (PDAC), one of the most lethal solid malignancies, characterized by poor responsiveness to chemotherapy. Recent clinical successes of direct KRAS inhibitors in other cancer types have renewed interest in KRAS-directed therapy for PDAC. However, early clinical experience has revealed often short-lived responses, highlighting the rapid emergence of resistance and the need to understand the mechanisms limiting durable benefit. This review summarizes current knowledge on molecular resistance to RAS-directed inhibitors in PDAC, organized into five categories: intrinsic resistance, KRAS-dependent mechanisms, KRAS-independent bypass signaling, downstream pathway reactivation, and tumor microenvironment (TME)-mediated resistance. Evidence from PDAC models is integrated with insights from other KRAS-driven malignancies, particularly non-small cell lung cancer, where direct KRAS inhibition has been studied extensively. Collectively, resistance appears to arise from layered adaptive processes rather than single alterations, including secondary KRAS mutations, receptor tyrosine kinase-driven bypass signaling, reactivation of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways, stromal-mediated protection, and reduced drug exposure. Notably, until recently, most evidence in PDAC has been indirect, while direct investigation of resistance mechanisms in KRAS-targeted settings has expanded rapidly only in recent years. Building on these advances, ongoing clinical trials increasingly explore rational combination strategies targeting upstream regulators, downstream effectors, and the TME. However, critical challenges persist, including patient selection, treatment sequencing, toxicity, and the lack of pharmacodynamic frameworks. Overcoming resistance will require mechanistically guided combinations, improved disease-specific models, and biomarker-driven adaptive strategies to ultimately achieve durable clinical benefits in PDAC.

Keywords

PDAC / G12D / G12V / EMT / tumor microenvironment / autophagy / Hippo pathway / MAPK pathway

References

[1] Stoop TF,Oba A.Pancreatic cancer.Lancet2025;405:1182-202

[2] Conroy T, Desseigne F, Ychou M, et al.; Groupe Tumeurs Digestives of Unicancer, PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.N Engl J Med2011;364:1817-25

[3] Barreto SG,O’Reilly EM,Zheng R.Pancreatic cancer-advances in the last 50 years.World J Surg2026;50:2106-15 PMCID:PMC13460810

[4] Provenzano PP,Chang AE,Von Hoff DD.Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma.Cancer Cell2012;21:418-29 PMCID:PMC3371414

[5] Özdemir BC,Carstens JL.Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival.Cancer Cell2014;25:719-34 PMCID:PMC4180632

[6] Waddell N, Pajic M, Patch AM, et al.; Australian Pancreatic Cancer Genome Initiative. Whole genomes redefine the mutational landscape of pancreatic cancer.Nature2015;518:495-501 PMCID:PMC4523082

[7] Digiacomo G,Garajova I,Cavazzoni A.Biological hallmarks and new therapeutic approaches for the treatment of PDAC.Life2021;11:843 PMCID:PMC8400856

[8] Collins MA,Zhang Y.Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice.J Clin Invest2012;122:639-53 PMCID:PMC3266788

[9] Jänne PA,Gadgeel SM.Adagrasib in non-small-cell lung cancer harboring a KRAS^G12C mutation.N Engl J Med2022;387:120-31

[10] Skoulidis F,Dy GK.Sotorasib for lung cancers with KRAS p.G12C mutation.N Engl J Med2021;384:2371-81 PMCID:PMC9116274

[11] Luo J.KRAS mutation in pancreatic cancer.Semin Oncol2021;48:10-8 PMCID:PMC8380752

[12] Strickler JH,George TJ.Sotorasib in KRAS p.G12C-mutated advanced pancreatic cancer.N Engl J Med2023;388:33-43 PMCID:PMC10506456

[13] Riedl JM,McNeil R.Emerging landscape of KRAS inhibitors in cancer treatment.Cancer Cell2026;44:471-97

[14] Adachi Y,Hayashi Y.Epithelial-to-mesenchymal transition is a cause of both intrinsic and acquired resistance to KRAS G12C inhibitor in KRAS G12C-mutant non-small cell lung cancer.Clin Cancer Res2020;26:5962-73

[15] Awad MM,Rybkin II.Acquired resistance to KRAS^G12C inhibition in cancer.N Engl J Med2021;384:2382-93 PMCID:PMC8864540

[16] Hou P,Zhang Q.Tumor microenvironment remodeling enables bypass of oncogenic KRAS dependency in pancreatic cancer.Cancer Discov2020;10:1058-77 PMCID:PMC7334087

[17] Hayes TK,Hu C.Long-term ERK inhibition in KRAS-mutant pancreatic cancer is associated with MYC degradation and senescence-like growth suppression.Cancer Cell2016;29:75-89 PMCID:PMC4816652

[18] Dilly J,Abbassi L.Mechanisms of resistance to oncogenic KRAS inhibition in pancreatic cancer.Cancer Discov2024;14:2135-61 PMCID:PMC11528210

[19] Than MT,Sor R.Cancer interception with KRAS inhibitors in preclinical models of pancreatic ductal adenocarcinoma.Science2026;391:1161-6

[20] Von Hoff DD,Arena FP.Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.N Engl J Med2013;369:1691-703 PMCID:PMC4631139

[21] Abbas AA,Gai J.Preliminary translational immune and stromal correlates in a randomized phase II trial of pembrolizumab with or without defactinib for resectable pancreatic ductal adenocarcinoma (PDAC).J Clin Oncol2023;41:4024

[22] Kessler D,Mantoulidis A.Drugging an undruggable pocket on KRAS.Proc Natl Acad Sci U S A2019;116:15823-9 PMCID:PMC6689897

[23] Bekaii-Saab TS,Spira AI.Adagrasib in advanced solid tumors harboring a KRAS^G12C mutation.J Clin Oncol2023;41:4097-106 PMCID:PMC10852394

[24] Lanman BA,Allen JG.Discovery of a covalent inhibitor of KRAS^G12C (AMG 510) for the treatment of solid tumors.J Med Chem2020;63:52-65

[25] Hallin J,Hargis L.The KRAS^G12C inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients.Cancer Discov2020;10:54-71 PMCID:PMC6954325

[26] Kemp SB,Markosyan N.Efficacy of a small-molecule inhibitor of KrasG12D in immunocompetent models of pancreatic cancer.Cancer Discov2023;13:298-311 PMCID:PMC9900321

[27] Mahadevan KK,LeBleu VS.KRAS^G12D inhibition reprograms the microenvironment of early and advanced pancreatic cancer to promote FAS-mediated killing by CD8⁺ T cells.Cancer Cell2023;41:1606-20.e8 PMCID:PMC10785700

[28] Hobbs GA,Miermont AM.Atypical KRAS^G12R mutant is impaired in PI3K signaling and macropinocytosis in pancreatic cancer.Cancer Discov2020;10:104-23 PMCID:PMC6954322

[29] Yadav V,Sharma S.Development of potent inhibitors against KRAS, its mutant G12R, allosteric and Switch-I/Switch-II site.In Silico Pharmacol2025;13:131 PMCID:PMC12423349

[30] Yang X,Han H.Abstract 4379: BPI-572270: An orally bioavailable and highly potent RAS (On) multi tri-complex inhibitor.Cancer Res2025;85:4379

[31] Spira AI,Kim DW.Preliminary safety, antitumor activity, and circulating tumor DNA (ctDNA) changes with RMC-9805, an oral, RAS(ON) G12D-selective tri-complex inhibitor in patients with KRAS G12D pancreatic ductal adenocarcinoma (PDAC) from a phase 1 study in advanced solid tumors.J Clin Oncol2025;43:724

[32] Arbour KC,Yaeger R.Abstract CT019: Preliminary safety and antitumor activity of zoldonrasib (RMC-9805), an oral, RAS(ON) G12D-selective, tri-complex inhibitor in patients with KRAS G12D non-small cell lung cancer (NSCLC) from a phase 1 study in advanced solid tumors.Cancer Res2025;85:CT019

[33] Lu S,Ai X.MA02.07 Efficacy and safety of GFH375 in advanced non-small cell lung cancer patients with KRAS G12D mutation.J Thorac Oncol2025;20:S59-60

[34] Zhou A,Sun Y.LBA84 Efficacy and safety of GFH375 monotherapy in previously treated advanced KRAS G12D-mutant pancreatic ductal adenocarcinoma (PDAC).Ann Oncol2025;36:S1626

[35] Garrido-Laguna I,Park W.Safety, efficacy, and on-treatment circulating tumor DNA (ctDNA) changes from a phase 1 study of RMC-6236, a RAS(ON) multi-selective, tri-complex inhibitor, in patients with RAS mutant pancreatic ductal adenocarcinoma (PDAC).J Clin Oncol2025;43:722

[36] Mitsunaga S,Machii K.Incidence and frequency of cancer cachexia during chemotherapy for advanced pancreatic ductal adenocarcinoma.Support Care Cancer2020;28:5271-9 PMCID:PMC7546994

[37] Khalil MA,Zahra Naqvi ME.Impact of cachexia on chemotherapy efficacy and survival in pancreatic cancer: a systematic review and meta-analysis.Cancer Control2024;31:10732748241292784 PMCID:PMC11483828

[38] Xue JY,Aronowitz J.Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition.Nature2020;577:421-5 PMCID:PMC7308074

[39] Misale S,Cortez E.KRAS G12C NSCLC models are sensitive to direct targeting of KRAS in combination with PI3K inhibition.Clin Cancer Res2019;25:796-807

[40] Cancer Genome Atlas Research Network. Integrated genomic characterization of pancreatic ductal adenocarcinoma.Cancer Cell2017;32:185-203.e13 PMCID:PMC5964983

[41] Chen Z,Walton Z.A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response.Nature2012;483:613-7 PMCID:PMC3385933

[42] Kang R,Zhang Q.RAGE is essential for oncogenic KRAS-mediated hypoxic signaling in pancreatic cancer.Cell Death Dis2014;5:e1480 PMCID:PMC4237264

[43] Shao DD,Krall EB.KRAS and YAP1 converge to regulate EMT and tumor survival.Cell2014;158:171-84 PMCID:PMC4110062

[44] Kapoor A,Ying H.Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer.Cell2014;158:185-97 PMCID:PMC4109295

[45] Rozengurt E.Crosstalk between KRAS, SRC and YAP signaling in pancreatic cancer: interactions leading to aggressive disease and drug resistance.Cancers2021;13:5126 PMCID:PMC8533944

[46] Drexler R,Wagner KC.The clinical relevance of the Hippo pathway in pancreatic ductal adenocarcinoma.J Cancer Res Clin Oncol2021;147:373-91 PMCID:PMC7817599

[47] Jin H,Bernards R.Rational combinations of targeted cancer therapies: background, advances and challenges.Nat Rev Drug Discov2023;22:213-34

[48] Vaclova T,Sherwood J.Concomitant KRAS mutations attenuate sensitivity of non-small cell lung cancer cells to KRAS G12C inhibition.Sci Rep2022;12:2699 PMCID:PMC8854729

[49] Koga T,Fujino T.KRAS secondary mutations that confer acquired resistance to KRAS G12C inhibitors, sotorasib and adagrasib, and overcoming strategies: insights from in vitro experiments.J Thorac Oncol2021;16:1321-32

[50] Tanaka N,Li C.Clinical acquired resistance to KRAS^G12C inhibition through a novel KRAS Switch-II pocket mutation and polyclonal alterations converging on RAS-MAPK reactivation.Cancer Discov2021;11:1913-22 PMCID:PMC8338755

[51] Yaeger R,Sinopoli J.Molecular characterization of acquired resistance to KRASG12C-EGFR inhibition in colorectal cancer.Cancer Discov2023;13:41-55 PMCID:PMC9827113

[52] Little AS,Sale MJ.Amplification of the driving oncogene, KRAS or BRAF, underpins acquired resistance to MEK1/2 inhibitors in colorectal cancer cells.Sci Signal2011;4:ra17

[53] Hofmann MH,Ramharter J.BI-3406, a potent and selective SOS1-KRAS interaction inhibitor, is effective in KRAS-driven cancers through combined MEK inhibition.Cancer Discov2021;11:142-57 PMCID:PMC7892644

[54] Fedele C,Teng KW.SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling.J Exp Med2021;218:e20201414 PMCID:PMC7549316

[55] Stites EC,Ma Z.Network analysis of oncogenic Ras activation in cancer.Science2007;318:463-7

[56] Sacher AG, Miller WH Jr, Patel MR, et al.; GO42144 Investigator Study group, GO42144 Investigator Study Group. Single-agent divarasib in patients with KRAS G12C-positive non-small cell lung cancer: long-term follow-up of a phase I study.J Clin Oncol2025;43:3249-53 PMCID:PMC12527784

[57] Murciano-Goroff YR,Heist RS.Pan-tumor activity of olomorasib, a next-generation KRAS G12C inhibitor in KRAS G12C-mutant advanced solid tumors: a first-in-human study.Nat Commun2026;17:3834 PMCID:PMC13121619

[58] O’Reilly EM,Pant S.Abstract LB337: Daraxonrasib monotherapy as first-line (1L) treatment for patients with metastatic pancreatic adenocarcinoma (mPDAC).Cancer Res2026;86:LB337

[59] O’Reilly EM, Wainberg ZA, Hendifar AE, et al.; RASolute 302 Trial Investigators. Daraxonrasib or chemotherapy in previously treated metastatic pancreatic cancer.N Engl J Med2026;395:325-37

[60] Ryan MB,Phat S.Vertical pathway inhibition overcomes adaptive feedback resistance to KRAS^G12C inhibition.Clin Cancer Res2020;26:1633-43 PMCID:PMC7124991

[61] Lito P,Yue J.Disruption of CRAF-mediated MEK activation is required for effective MEK inhibition in KRAS mutant tumors.Cancer Cell2014;25:697-710 PMCID:PMC4049532

[62] Gulay KCM,Pantazopoulou V.Dual inhibition of KRASG12D and Pan-ERBB is synergistic in pancreatic ductal adenocarcinoma.Cancer Res2023;83:3001-12 PMCID:PMC10502451

[63] Ambrogio C,Zhou ZW.KRAS dimerization impacts MEK inhibitor sensitivity and oncogenic activity of mutant KRAS.Cell2018;172:857-68.e15

[64] Chen PY,Dorans KJ.Adaptive and reversible resistance to kras inhibition in pancreatic cancer cells.Cancer Res2018;78:985-1002 PMCID:PMC5837062

[65] Turke AB,Costa C.MEK inhibition leads to PI3K/AKT activation by relieving a negative feedback on ERBB receptors.Cancer Res2012;72:3228-37 PMCID:PMC3515079

[66] Alanazi FE,Alattar A,Kotb AA.Broad-spectrum RAS inhibition in pancreatic ductal adenocarcinoma: mechanistic advances and therapeutic promise.Pharmaceuticals2025;18:1788 PMCID:PMC12735763

[67] Suzuki S,Teramura T.KRAS inhibitor resistance in MET-amplified KRAS^G12C non-small cell lung cancer induced by RAS- and non-RAS-mediated cell signaling mechanisms.Clin Cancer Res2021;27:5697-707

[68] Wu H,Zhang H.Coexpression of EGFR and CXCR4 predicts poor prognosis in resected pancreatic ductal adenocarcinoma.PLoS One2015;10:e0116803 PMCID:PMC4332630

[69] Neuzillet C,Tijeras-Raballand A.High c-Met expression in stage I-II pancreatic adenocarcinoma: proposal for an immunostaining scoring method and correlation with poor prognosis.Histopathology2015;67:664-76

[70] Kim JH,Kim BJ,Jang HJ.Prognostic value of c-Met overexpression in pancreatic adenocarcinoma: a meta-analysis.Oncotarget2017;8:73098-104 PMCID:PMC5641195

[71] Dong XD,Cai CY.Overexpression of ABCB1 associated with the resistance to the KRAS-G12C specific inhibitor ARS-1620 in cancer cells.Front Pharmacol2022;13:843829 PMCID:PMC8905313

[72] Rijmers J,Bui V.ABCB1 attenuates brain exposure to the KRAS^G12C inhibitor opnurasib whereas binding to mouse carboxylesterase 1c influences its plasma exposure.Biomed Pharmacother2024;175:116720

[73] Tian H,Zhou Z.SRC at the crossroads of KRAS inhibitor resistance: mechanisms and therapeutic opportunities.Cancer Lett2026;639:218194

[74] Brown WS,Nemirovsky O.Overcoming adaptive resistance to KRAS and MEK inhibitors by co-targeting mTORC1/2 complexes in pancreatic cancer.Cell Rep Med2020;1:100131 PMCID:PMC7691443

[75] O’Neil BH,Ma WW.A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer.Ann Oncol2015;26:1923-9 PMCID:PMC4551155

[76] Wang J,Barve M.224 (PB104) - Preliminary results from HERKULES-1: a phase 1b/2, open-label, multicenter study of ERAS-007, an oral ERK1/2 inhibitor, in patients with advanced or metastatic solid tumors.Eur J Cancer2022;174:S80-1

[77] Bodoky G,Spigel DR.A phase II open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy.Invest New Drugs2012;30:1216-23

[78] Infante JR,Park JO.A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas.Eur J Cancer2014;50:2072-81

[79] Lim K,Safyan RA.Avutometinib/defactinib and gemcitabine/nab-paclitaxel combination in first-line metastatic pancreatic ductal adenocarcinoma: initial safety and efficacy of phase 1b/2 study (RAMP 205).J Clin Oncol2024;42:4140

[80] Bryant KL,Kimmelman AC.KRAS: feeding pancreatic cancer proliferation.Trends Biochem Sci2014;39:91-100 PMCID:PMC3955735

[81] Khan N,Ali Zaidi SA.Drugging the ‘undruggable’ KRAS: breakthroughs, challenges, and opportunities in pancreatic cancer.Cancer Biol Med2025;22:762-88 PMCID:PMC12302276

[82] Kinsey CG,Boespflug AM.Protective autophagy elicited by RAF→MEK→ERK inhibition suggests a treatment strategy for RAS-driven cancers.Nat Med2019;25:620-7 PMCID:PMC6452642

[83] Recouvreux MV,Zhang Y.Glutamine mimicry suppresses tumor progression through asparagine metabolism in pancreatic ductal adenocarcinoma.Nat Cancer2024;5:100-13 PMCID:PMC10956382

[84] Rozeveld CN,Zhang L.KRAS controls pancreatic cancer cell lipid metabolism and invasive potential through the lipase HSL.Cancer Res2020;80:4932-45 PMCID:PMC7669720

[85] Santana-Codina N,Zhang Y.Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis.Nat Commun2018;9:4945 PMCID:PMC6251888

[86] Ma J,Tan J.Mechanistic foundations of KRAS-driven tumor ecosystems: integrating crosstalk among immune, metabolic, microbial, and stromal microenvironment.Adv Sci2025;12:e02714 PMCID:PMC12376694

[87] Moore MJ, Hamm J, Dancey J, et al.; National Cancer Institute of Canada Clinical Trials Group. Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced or metastatic adenocarcinoma of the pancreas: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group.J Clin Oncol2003;21:3296-302

[88] Bramhall SR, Rosemurgy A, Brown PD, Bowry C, Buckels JA; Marimastat Pancreatic Cancer Study Group. Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial.J Clin Oncol2001;19:3447-55

[89] Catenacci DV,Karrison T.Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer.J Clin Oncol2015;33:4284-92 PMCID:PMC4678179

[90] Hingorani SR,Bullock AJ.HALO 202: Randomized phase II study of PEGPH20 plus nab-paclitaxel/gemcitabine versus nab-paclitaxel/gemcitabine in patients with untreated, metastatic pancreatic ductal adenocarcinoma.J Clin Oncol2018;36:359-66

[91] Ramanathan RK,Philip PA.Phase IB/II randomized study of FOLFIRINOX plus pegylated recombinant human hyaluronidase versus FOLFIRINOX alone in patients with metastatic pancreatic adenocarcinoma: SWOG S1313.J Clin Oncol2019;37:1062-9 PMCID:PMC6494359

[92] Van Cutsem E, Tempero MA, Sigal D, et al.; HALO 109-301 Investigators. Randomized phase III trial of pegvorhyaluronidase alfa with nab-paclitaxel plus gemcitabine for patients with hyaluronan-high metastatic pancreatic adenocarcinoma.J Clin Oncol2020;38:3185-94 PMCID:PMC7499614

[93] Biondani G,Greco MR.Extracellular matrix composition modulates PDAC parenchymal and stem cell plasticity and behavior through the secretome.FEBS J2018;285:2104-24

[94] Di Maggio F,Delvecchio FR.Pancreatic stellate cells regulate blood vessel density in the stroma of pancreatic ductal adenocarcinoma.Pancreatology2016;16:995-1004 PMCID:PMC5123629

[95] McAndrews KM,Stalnecker CA.An allele-agnostic mutant-KRAS inhibitor suppresses tumor maintenance signals and reprograms tumor immunity in pancreatic cancer.Sci Transl Med2025;17:eadt5511 PMCID:PMC12742855

[96] Rebelo R,Giovannetti E.Fibroblasts in pancreatic cancer: molecular and clinical perspectives.Trends Mol Med2023;29:439-53

[97] Geng X,Zhao L.Cancer-associated fibroblast (CAF) heterogeneity and targeting therapy of CAFs in pancreatic cancer.Front Cell Dev Biol2021;9:655152 PMCID:PMC8319605

[98] Pereira BA,Papanicolaou M.CAF subpopulations: a new reservoir of stromal targets in pancreatic cancer.Trends Cancer2019;5:724-41

[99] Liu X,Stone ML.Stromal reprogramming overcomes resistance to RAS-MAPK inhibition to improve pancreas cancer responses to cytotoxic and immune therapy.Sci Transl Med2024;16:eado2402 PMCID:PMC12376167

[100] Wasko UN,Dalton TC.Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer.Nature2024;629:927-36 PMCID:PMC11111406

[101] Jiang H,Knolhoff BL.Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy.Nat Med2016;22:851-60 PMCID:PMC4935930

[102] Lander VE,Kingston NL.Stromal reprogramming by FAK inhibition overcomes radiation resistance to allow for immune priming and response to checkpoint blockade.Cancer Discov2022;12:2774-99 PMCID:PMC9722639

[103] Lencioni G,Toledo B.Unravelling the complexities of resistance mechanism in pancreatic cancer: insights from in vitro and ex-vivo model systems.Semin Cancer Biol2024;106-7:217-33

[104] Mulero-Sánchez A,Visuvasam B.CRISPR knockout screens reveal JUN as the master mediator of resistance to MAPK inhibition in KRAS-mutant pancreatic cancer.J Exp Clin Cancer Res2026;45:60 PMCID:PMC12947432

[105] Vahabi M,Centra C,Morelli L.Thinking small to win big? A critical review on the potential application of extracellular vesicles for biomarker discovery and new therapeutic approaches in pancreatic cancer.Semin Cancer Biol2023;97:50-67

[106] Haldar SD,Hong SJ.Phase I trial of binimetinib plus hydroxychloroquine in patients with previously treated metastatic pancreatic cancer.Oncologist2026;31:oyag071 PMCID:PMC13006057

[107] Ghanwatkar Y,Chittipolu A,Shrestha P.Dual inhibition of KRAS G12D and PI3K/BRD4 signaling overcomes therapeutic resistance in pancreatic cancer.Acta Biomater2026;212:637-54 PMCID:PMC13207627

[108] Yang K,Wang Y.Targeting class I HDACs suppresses oncogenic vulnerabilities and potentiates KRAS/MAPK pathway inhibitors in KRAS-mutant cancers.J Adv Res2026;In Press:

[109] Paulsohn MB,Schlösser D.Simultaneous targeting of KRAS and CDK4 synergistically induces durable growth arrest in pancreatic cancer cells.Cell Death Dis2025;17:129 PMCID:PMC12847887

[110] Xu X,Xu R.Combination of PARP and KRAS^G12D inhibitors enhances therapeutic efficacy by exploiting vulnerabilities in PDAC.Nat Commun2026;17:3118 PMCID:PMC13043926

[111] Miyan J,Cao L.The combination of a BCL-xL PROTAC and an mTOR inhibitor sensitizes pancreatic ductal adenocarcinoma to KRAS^G12D inhibitor treatment.Cancers2026;18:920 PMCID:PMC13025216

[112] Park W,Spira AI.Setidegrasib in advanced non-small-cell lung cancer and pancreatic cancer.N Engl J Med2026;394:1409-20

[113] Liang J,Zhang Y,Zheng Y.Systematic and precise interventions for KRAS-mutant cancers.Exp Hematol Oncol2026;15:33 PMCID:PMC13003733

[114] Arbour K,Garrido-Laguna I.652O Preliminary clinical activity of RMC-6236, a first-in-class, RAS-selective, tri-complex RAS-MULTI(ON) inhibitor in patients with KRAS mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC).Ann Oncol2023;34:S458

[115] Jiang J,Maldonato BJ.Translational and therapeutic evaluation of RAS-GTP inhibition by RMC-6236 in RAS-driven cancers.Cancer Discov2024;14:994-1017 PMCID:PMC11149917

[116] Kim D,Rudolph D.Pan-KRAS inhibitor disables oncogenic signalling and tumour growth.Nature2023;619:160-6 PMCID:PMC10322706