Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer
Broad Institute · Harvard University · +11 more institutions
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,…
Citation impact
- FWCI
- 47.52
- Percentile
- 100%
- References
- 100
Authors
55- JDJulien DillyCorresponding
Broad Institute, Harvard University, Dana-Farber Cancer Institute
- MTMegan T. Hoffman
Harvard University, Dana-Farber Cancer Institute
- LALaleh Abbassi
Broad Institute, Harvard University, Dana-Farber Cancer Institute
- ZLZiyue Li
Broad Institute, Dana-Farber Cancer Institute
- FPFrancesca Paradiso
The University of Texas MD Anderson Cancer Center
Topics & keywords
- KRAS
- Pancreatic cancer
- Cancer research
- Resistance (ecology)
- Cancer
- Biology
- Bioinformatics
- Genetics
- Good health and well-being
Funding
- HFHale Family Center for Pancreatic Cancer Research
- PCPancreatic Cancer Action Network
- BSBristol-Myers Squibb
- LFLustgarten Foundation
- BFBarr Foundation
- SFSociety for Immunotherapy of Cancer
- BTBreak Through Cancer
- MTMirati Therapeutics
- NINational Institutes of HealthAwards: R01CA218230, P50CA221707, K08 CA260442, P50CA127003, R01AI158488
- LCLudwig Center at Harvard
- NCNational Cancer InstituteAwards: U01 CA274276, K08 CA260442, P50CA221707, R01CA218230, R01 CA276268, P50CA127003