Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer.

Autor:	Dilly J; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Hoffman MT; Harvard Medical School, Boston, Massachusetts.; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts., Abbassi L; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Li Z; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts., Paradiso F; Department of Translational Molecular Pathology, Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas., Parent BD; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts., Hennessey CJ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts., Jordan AC; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts., Morgado M; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Dasgupta S; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Uribe GA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts., Yang A; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts., Kapner KS; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts., Hambitzer FP; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts., Qiang L; Harvard Medical School, Boston, Massachusetts.; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts., Feng H; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Geisberg J; Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Wang J; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Evans KE; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Lyu H; Therapeutics Discovery Division, TRACTION Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas., Schalck A; Therapeutics Discovery Division, TRACTION Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas., Feng N; Therapeutics Discovery Division, TRACTION Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas., Lopez AM; Therapeutics Discovery Division, TRACTION Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas., Bristow CA; Therapeutics Discovery Division, TRACTION Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas., Kim MP; Therapeutics Discovery Division, TRACTION Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas., Rajapakshe KI; Department of Translational Molecular Pathology, Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas., Bahrambeigi V; Department of Translational Molecular Pathology, Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas., Roth JA; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts., Garg K; Exact Sciences, Redwood City, California., Guerrero PA; Department of Translational Molecular Pathology, Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas., Stanger BZ; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Cristea S; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.; Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard School of Public Health, Boston, Massachusetts., Lowe SW; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York., Baslan T; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Van Allen EM; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Mancias JD; Harvard Medical School, Boston, Massachusetts.; Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Chan E; Amgen Inc., Thousand Oaks, California., Anderson A; Amgen Inc., Thousand Oaks, California., Katlinskaya YV; Amgen Inc., Thousand Oaks, California., Shalek AK; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.; Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts.; Institute for Medical Engineering and Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts., Hong DS; University of Texas M.D. Anderson Cancer Center, Houston, Texas., Pant S; University of Texas M.D. Anderson Cancer Center, Houston, Texas., Hallin J; Mirati Therapeutics Inc., San Diego, California., Anderes K; Mirati Therapeutics Inc., San Diego, California., Olson P; Mirati Therapeutics Inc., San Diego, California., Heffernan TP; Therapeutics Discovery Division, TRACTION Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas., Chugh S; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Christensen JG; Mirati Therapeutics Inc., San Diego, California., Maitra A; Department of Translational Molecular Pathology, Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas., Wolpin BM; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts.; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts., Raghavan S; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.; Harvard Medical School, Boston, Massachusetts.; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts., Nowak JA; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts., Winter PS; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts., Dougan SK; Harvard Medical School, Boston, Massachusetts.; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts., Aguirre AJ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.; Harvard Medical School, Boston, Massachusetts.; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2024 Nov 01; Vol. 14 (11), pp. 2135-2161.
DOI:	10.1158/2159-8290.CD-24-0177
Abstrakt:	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. (©2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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