Abstract 1943: Discovery and characterization of potential drivers of resistance to the KRAS G12D inhibitor, MRTX1133, in cancer cell line models

Abstract Introduction: KRASG12D is the most common KRAS mutation and is present in approximately 34% of pancreatic cancer, 10-12% of colorectal cancer, 4% of lung adenocarcinoma and in a number of other cancer types. We previously identified MRTX1133, a potent, selective, and non-covalent KRASG12D inhibitor. The advancement of MRTX1133 to clinical trials warrants continued study of the role of the KRASG12D mutation in cancer pathogenesis and progression. Methods: Previous pharmacodynamic and pharmacogenomic profiling in sensitive and partially resistant models identified mechanisms implicated in limiting the anti-tumor response including signaling pathways that induce feedback reactivation and/or bypass KRAS dependence. Thus, cell lines (GP2D and SNU-1033, colorectal cancer; HPAC and AsPC-1, pancreatic cancer) were utilized to study acquired resistance to MRTX1133 following continuous treatment at increasing concentrations over time. These cell lines were confirmed to be stably resistant as determined by evaluation of response to MRTX1133 in vitro and in vivo. These cell lines were extensively profiled to determine underlying mechanisms of resistance utilizing molecular profiling strategies as well as drug combination screens to interrogate pathways that could circumvent resistance. Results: In one of the four generated cell lines with acquired resistance, evidence of secondary KRAS mutations Y96N and H95Q were confirmed by RNAseq and are likely drivers of resistance in this cell line and are consistent with known mechanisms of KRASG12C inhibitor resistance. The three other MRTX1133 resistant cell lines did not show evidence of secondary KRAS mutations and were further evaluated for mechanisms that bypass KRAS dependence. Combinations of MRTX1133 with therapies that target pathways including upstream RTK signaling, mTOR, or AKT broadly enhanced the anti-tumor activity of MRTX1133 in both in vitro cell viability and in vivo efficacy studies in the resistant cell lines. Conclusion: Collectively, these data provide early insight onto potential mechanisms of resistance to selective KRASG12D inhibitors and demonstrate the importance of developing rational combination strategies designed to address drug resistance. In addition, these studies provide a catalogue of potentially druggable vulnerabilities that complement KRAS blockade. Citation Format: Xousaen M. Helu, Ellie Griffiths, Andrew Calinisan, Allan Hebbert, Larry Yan, Natalie Hoffman, David Trinh, Laura Hover, Julio Fernandez-Banet, David M. Briere, Ella Lifset, Peter Olson, James G. Christensen, Jill Hallin. Discovery and characterization of potential drivers of resistance to the KRAS G12D inhibitor, MRTX1133, in cancer cell line models abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 1943.