Supplemental Table 5 from Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer

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posted on 2024-11-01, 07:40 authored by Julien Dilly, Megan T. Hoffman, Laleh Abbassi, Ziyue Li, Francesca Paradiso, Brendan D. Parent, Connor J. Hennessey, Alexander C. Jordan, Micaela Morgado, Shatavisha Dasgupta, Giselle A. Uribe, Annan Yang, Kevin S. Kapner, Felix P. Hambitzer, Li Qiang, Hanrong Feng, Jacob Geisberg, Junning Wang, Kyle E. Evans, Hengyu Lyu, Aislyn Schalck, Ningping Feng, Anastasia M. Lopez, Christopher A. Bristow, Michael P. Kim, Kimal I. Rajapakshe, Vahid Bahrambeigi, Jennifer A. Roth, Kavita Garg, Paola A. Guerrero, Ben Z. Stanger, Simona Cristea, Scott W. Lowe, Timour Baslan, Eliezer M. Van Allen, Joseph D. Mancias, Emily Chan, Abraham Anderson, Yuliya V. Katlinskaya, Alex K. Shalek, David S. Hong, Shubham Pant, Jill Hallin, Kenna Anderes, Peter Olson, Timothy P. Heffernan, Seema Chugh, James G. Christensen, Anirban Maitra, Brian M. Wolpin, Srivatsan Raghavan, Jonathan A. Nowak, Peter S. Winter, Stephanie K. Dougan, Andrew J. Aguirre

Supplemental Table 5A: Drug sensitivity metrics from MRTX1133-treated KRAS^G12D patient-derived organoids. Supplemental Table 5B: MRTX1133 dose response across KRAS^G12D mutated patient-derived organoids.

Funding

Break Through Cancer (BTC)

National Cancer Institute (NCI)

United States Department of Health and Human Services

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Hale Family Center for Pancreatic Cancer Research (Hale Family Research Center At Dana-Farber Cancer Institute)

Lustgarten Foundation (The Lustgarten Foundation)

Pancreatic Cancer Action Network (PCAN)

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ARTICLE 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

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Keywords

Oncogenes & Tumor Suppressors Kras

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