ArticleCancer discovery2024
Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer.
Registry-linked trialAbstract read
In one paragraph
Article in Cancer discovery, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT03600883 (A Phase 1/2, Open-label Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of Sotorasib), which is not on this map. Cited by 186 papers.
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186citing papers in PubMed
–field-weighted citation impact
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Phase 1/2, Open-label Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of Sotorasib (AMG 510) Monotherapy in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation and Sotorasib (AMG 510) Combination Therapy in Subjects With Advanced NSCLC With KRAS p.G12C Mutation (CodeBreaK 100)
Who cites it
186 citing papers in PubMed.
- Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer.Nature medicine · 2026Trial
- Gemcitabine and nab-paclitaxel with or without the VDR agonist paricalcitol for metastatic pancreatic cancer: a randomized, multiarm, run-in phase trial.Nature cancer · 2026Trial
- A Phase II Trial of an Extended-Release siRNA Implant Targeting KRASG12D/V in Locally Advanced Pancreatic Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Trial
- Open-Label, Phase II Trial of Extracellular Regulated Kinase Inhibition Alone and in Combination With Autophagy Inhibition in Patients With Metastatic Pancreatic Cancer.JCO precision oncology · 2025Trial
- Concurrent EGFR exon 19 deletion-insertion and germline BRCA1 alteration in KRAS-wild-type pancreatic ductal adenocarcinoma: A case report and review of therapeutic implications.Oncology letters · 2026Article
- Pancreatic Cancer KRAS Breakthrough: Drug Graveyard No More.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- Radical Antegrade Modular Pancreatosplenectomy Versus Standard Resection in T3 Body and Tail Pancreatic Ductal Adenocarcinoma: A Multicenter Retrospective Cohort Study.Annals of surgical oncology · 2026Article
- Targeting Oncomucin-Driven Immunosuppression Improves the Efficacy of K-rasGastroenterology · 2026Article
- Baseline cellular state shapes the molecular impact of mutant Kirsten rat sarcoma viral oncogene homologue (KRAS) alleles in reconstituted pancreatic cancer cells.Molecular omics · 2026Article
- Review
- Overcoming cancer resistance in pancreatic cancer: toward dynamic precision oncology.Molecular biology reports · 2026Review
- Thermal Stability, Plasma Pharmacokinetics, and Tumor Response Modeling of a Cell-Penetrating Protein That Cleaves RAS Family GTPases.ACS pharmacology & translational science · 2026Article
- KRAS Inhibitor-Induced Cancer Cell Death Enhances Sensitivity to Immune-Mediated Bystander Killing of Drug-Resistant Subclones.Cancer research · 2026Article
- RAS-targeted therapies for pancreatic cancer.ESMO gastrointestinal oncology · 2026Review
- Landscape of acquired resistance alterations in gastrointestinal malignancies after genomically targeted therapy.Journal of gastrointestinal oncology · 2026Article
- Dual Targeting of FGFR4 and PI3K-mTOR Suppresses Tumor-Associated Phenotypes in Pancreatic Ductal Adenocarcinoma.International journal of molecular sciences · 2026Article
- Genetic Drivers of Sensitivity or Resistance to RAS(ON) Multiselective Inhibitors in NRAS-Mutated Melanoma.Cancer research · 2026Article
- Targeted KRASG12V Degradation In Vivo Elicits Lung Adenocarcinoma Regression with Subsequent Relapse from Dysregulated Proteolysis.Cancer research · 2026Article
- Article
- PI3K Regulates Wild-type RAS Signaling to Confer Resistance to KRAS Inhibition.Cancer research · 2026Article
126 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
55 authors.
Julien Dilly *Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.ORCID 0000-0002-4006-5285
Megan T Hoffman *Harvard Medical School, Boston, Massachusetts.ORCID 0000-0003-0907-9977
Laleh Abbassi *Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.ORCID 0000-0003-0404-9736
Ziyue Li *Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.ORCID 0000-0001-7065-9546
Francesca Paradiso *Department of Translational Molecular Pathology, Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0001-6926-1119
Brendan D ParentDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.ORCID 0009-0001-8258-1755
Connor J HennesseyDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.ORCID 0000-0002-5579-1220
Alexander C JordanDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.ORCID 0000-0002-3006-7033
Micaela MorgadoDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.ORCID 0000-0002-0390-5812
Shatavisha DasguptaDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.ORCID 0000-0003-1804-5015
Giselle A UribeDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.ORCID 0000-0003-1523-6916
Annan YangDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.ORCID 0009-0002-4676-6717
Kevin S KapnerDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.ORCID 0000-0002-2306-2373
Felix P HambitzerDepartment of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts.ORCID 0000-0001-7759-5071
Li QiangHarvard Medical School, Boston, Massachusetts.ORCID 0000-0002-2354-177X
Hanrong FengDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.ORCID 0000-0002-2133-5374
Jacob GeisbergDepartment of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts.ORCID 0009-0009-5786-9771
Junning WangDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.ORCID 0000-0002-5559-9343
Kyle E EvansDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.ORCID 0000-0002-6246-9520
Hengyu LyuTherapeutics Discovery Division, TRACTION Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0003-1093-9364
Aislyn SchalckTherapeutics Discovery Division, TRACTION Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-4020-1822
Ningping FengTherapeutics Discovery Division, TRACTION Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0003-1917-9648
Anastasia M LopezTherapeutics Discovery Division, TRACTION Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0009-0005-7264-2859
Christopher A BristowTherapeutics Discovery Division, TRACTION Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0009-0009-9266-6849
Michael P KimTherapeutics Discovery Division, TRACTION Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-8269-854X
Kimal I RajapaksheDepartment of Translational Molecular Pathology, Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-0472-858X
Vahid BahrambeigiDepartment of Translational Molecular Pathology, Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-7964-6087
Jennifer A RothThe Broad Institute of Harvard and MIT, Cambridge, Massachusetts.ORCID 0000-0002-5117-5586
Kavita GargExact Sciences, Redwood City, California.ORCID 0009-0009-7361-4699
Paola A GuerreroDepartment of Translational Molecular Pathology, Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-7345-1246
Ben Z StangerDepartment of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.ORCID 0000-0003-0410-4037
Simona CristeaThe Broad Institute of Harvard and MIT, Cambridge, Massachusetts.ORCID 0009-0003-1276-186X
Scott W LoweCancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.ORCID 0000-0002-5284-9650
Timour BaslanDepartment of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.ORCID 0009-0008-2632-0586
Eliezer M Van AllenDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.ORCID 0000-0002-0201-4444
Joseph D ManciasHarvard Medical School, Boston, Massachusetts.ORCID 0000-0002-0692-3717
Emily ChanAmgen Inc., Thousand Oaks, California.ORCID 0009-0008-7042-7217
Abraham AndersonAmgen Inc., Thousand Oaks, California.ORCID 0000-0002-1624-622X
Yuliya V KatlinskayaAmgen Inc., Thousand Oaks, California.ORCID 0009-0003-5647-4782
Alex K ShalekThe Broad Institute of Harvard and MIT, Cambridge, Massachusetts.ORCID 0000-0001-5670-8778
David S HongUniversity of Texas M.D. Anderson Cancer Center, Houston, Texas.ORCID 0000-0001-8721-1609
Shubham PantUniversity of Texas M.D. Anderson Cancer Center, Houston, Texas.ORCID 0000-0001-9281-480X
Jill HallinMirati Therapeutics Inc., San Diego, California.ORCID 0000-0002-8443-7116
Kenna AnderesMirati Therapeutics Inc., San Diego, California.ORCID 0000-0002-4515-2011
Peter OlsonMirati Therapeutics Inc., San Diego, California.ORCID 0009-0008-5164-8102
Timothy P HeffernanTherapeutics Discovery Division, TRACTION Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-3166-8922
Seema ChughDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.ORCID 0000-0003-1486-0725
James G ChristensenMirati Therapeutics Inc., San Diego, California.ORCID 0000-0003-1835-0335
Anirban MaitraDepartment of Translational Molecular Pathology, Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0001-7923-9978
Brian M WolpinDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.ORCID 0000-0002-0455-1032
Srivatsan Raghavan *Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.ORCID 0000-0002-5374-9918
Jonathan A Nowak *Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.ORCID 0000-0002-0943-7407
Peter S Winter *The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.ORCID 0000-0002-6557-3219
Stephanie K Dougan *Harvard Medical School, Boston, Massachusetts.ORCID 0000-0002-2263-363X
Andrew J Aguirre *Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.ORCID 0000-0002-0701-6203
Funding
X-RAY CRYSTALLOGRAPHYP30CA008748 · NCI · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI SELWYN M VICKERS · 1985 to 2026
$347.4MTissue and Pathology ResourcesP50CA127003 · NCI · DANA-FARBER CANCER INST · PI SHIVDASANI, RAMESH A · 2007 to 2023
$33.2MPhysician Scientist Training in Cancer ResearchT32CA009172 · NCI · DANA-FARBER CANCER INSTITUTE · PI Jennifer R Brown, James A. DeCaprio · 1985 to 2026
$17.1MProject 3: Inhibiting Oxidative Phosphorylation in Pancreatic CancerP50CA221707 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI KOPETZ, SCOTT · 2019 to 2023
$11.0MStromal modulation of pancreatic cancer malignant cell state and therapeutic sensitivityU01CA274276 · NCI · DANA-FARBER CANCER INST · PI Andrew James Aguirre, Stephanie Dougan · 2022 to 2026
$5.1MLongitudinal therapeutic monitoring of colorectal cancer patients using exosome-based liquid biopsiesR01CA218230 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI KOPETZ, SCOTT, MAITRA, ANIRBAN · 2018 to 2022
$3.3MMolecular Pathways Regulating Tissue-resident Memory T cells in the GutR01AI169188 · NIAID · MASSACHUSETTS GENERAL HOSPITAL · PI Michael Lawrence Dougan · 2022 to 2026
$3.0MCDK4/6 inhibition during CD8 T cell priming potentiates memory formation in mice and humansR01AI158488 · NIAID · DANA-FARBER CANCER INST · PI DOUGAN, STEPHANIE · 2021 to 2025
$2.2MMechanisms of response and resistance to KRAS inhibition in pancreatic cancerR01CA276268 · NCI · DANA-FARBER CANCER INST · PI Andrew James Aguirre · 2023 to 2026
$2.2MRegulation and targeting of tumor cell states and plasticity in pancreatic cancerK08CA260442 · NCI · DANA-FARBER CANCER INST · PI Srivatsan Raghavan · 2022 to 2026
$1.5MBreak Through Cancer (BTC)Hale Family Center for Pancreatic Cancer Research (Hale Family Research Center At Dana-Farber Cancer Institute)Lustgarten Foundation (The Lustgarten Foundation)National Cancer Institute (NCI) P50CA127003National Cancer Institute (NCI) P50CA221707NCI NIH HHS K08 CA260442NCI NIH HHS P30 CA008748NCI NIH HHS P50 CA127003NCI NIH HHS P50 CA221707NCI NIH HHS R01 CA218230NCI NIH HHS R01 CA276268NCI NIH HHS T32 CA009172NCI NIH HHS U01 CA274276NIAID NIH HHS R01 AI158488NIAID NIH HHS R01 AI169188Pancreatic Cancer Action Network (PCAN)
Abstract
KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the KrasLSL-G12D/+; Trp53LSL-R172H/+; p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras, Yap1, Myc, Cdk6, and Abcb1a/b, and co-evolution of drug-resistant transcriptional programs. Moreover, in KPC and PDX models, mesenchymal and basal-like cell states displayed increased response to KRAS inhibition compared to the classical state. Combination treatment with KRASG12D inhibition and chemotherapy significantly improved tumor control in PDAC mouse models. Collectively, these data elucidate co-evolving resistance mechanisms to KRAS inhibition and support multiple combination therapy strategies. Significance: Acquired resistance may limit the impact of KRAS inhibition in patients with PDAC. Using clinical samples and multiple preclinical models, we define heterogeneous genetic and non-genetic mechanisms of resistance to KRAS inhibition that may guide combination therapy approaches to improve the efficacy and durability of these promising therapies for patients. See related commentary by Marasco and Misale, p. 2018.
Indexed as
Drug Resistance, NeoplasmPancreatic NeoplasmsProto-Oncogene Proteins p21(ras)AnimalsCarcinoma, Pancreatic DuctalCell Line, TumorHumansMiceMutationPyrimidinesKRAS protein, humanProto-Oncogene Proteins p21(ras)Pyrimidines
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LicenceCC BY-NC-ND
Read underepoch 390
Registered trials
NCT03600883ClinicalTrials.gov
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.