<\/p>\n\n\n\n
Analysis of clinical samples from patients with pancreatic cancer and preclinical models treated with KRAS inhibitors identifies diverse mechanisms of resistance and yields new insights for developing combination therapy strategies.<\/p>\n\n\n\n
KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRAS<\/em>G12C<\/sup>-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA<\/em> and KRAS<\/em>, and amplifications of KRAS<\/em>G12C<\/em><\/sup>, MYC<\/em>, MET<\/em>, EGFR<\/em>, and CDK6<\/em> emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D<\/sup> inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the Kras<\/em>LSL-G12D\/+<\/sup>; Trp53<\/em>LSL-R172H\/+<\/sup>; p48-Cre<\/em> (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras<\/em>, Yap1<\/em>, Myc<\/em>, Cdk6, and Abcb1a\/b<\/em>, 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<\/sup> 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.<\/p>\n","protected":false},"excerpt":{"rendered":" Analysis of clinical samples from patients with pancreatic cancer and preclinical models treated with KRAS inhibitors identifies diverse mechanisms of resistance and yields new insights for developing combination therapy strategies. 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 […]<\/p>\n","protected":false},"featured_media":0,"template":"","meta":{"msr-url-field":"","msr-podcast-episode":"","msrModifiedDate":"","msrModifiedDateEnabled":false,"ep_exclude_from_search":false,"_classifai_error":"","msr-author-ordering":[{"type":"text","value":"Julien Dilly","user_id":0},{"type":"text","value":"Megan T. Hoffman","user_id":0},{"type":"text","value":"Laleh Abbassi","user_id":0},{"type":"text","value":"Zi-Yue Li","user_id":0},{"type":"text","value":"Francesca Paradiso","user_id":0},{"type":"text","value":"Brendan D. Parent","user_id":0},{"type":"text","value":"Connor J. Hennessey","user_id":0},{"type":"text","value":"Alexander C. Jordan","user_id":0},{"type":"text","value":"Micaela Morgado","user_id":0},{"type":"text","value":"Shatavisha Dasgupta","user_id":0},{"type":"text","value":"Giselle A. 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