Abstract 1131: Pharmacogenomic insight into targetable vulnerabilities and modifiers of response to MRTX1133 in KRASG12D-mutant models

Abstract The ability to effectively target mutated KRAS has remained elusive despite decades of research. Recently, the identification of selective KRASG12C inhibitors has provided an effective treatment option for patients harboring this particular mutation and has also provided insight toward targeting other KRAS mutants, including KRASG12D. MRTX1133 was identified via a structure-based drug design strategy as a potent, selective, and non-covalent KRASG12D inhibitor directed at the switch II binding pocket. MRTX1133 exhibited dose dependent KRAS pathway and tumor growth inhibition and demonstrated marked anti-tumor activity across a panel of models in vivo, including tumor regression >30% in 8 out of 11 pancreatic ductal adenocarcinoma (PDAC) models. While evaluation of MRTX1133 across a panel of cell and patient-derived xenograft models demonstrated strong single agent activity in the majority of models tested, a subset of models were less responsive. Focused sgRNA libraries targeting ~5,000 genes were tested in MRTX1133-anchored CRISPR/Cas9 screens in vitro and in vivo in PDAC and colorectal KRASG12D-mutant cell lines. Similar to what was seen in a targeted genetic screen with our selective KRASG12C inhibitor MRTX849, several genes that act either upstream or downstream of KRAS were depleted with MRTX1133 treatment which illuminate specific targetable vulnerabilities in the context of KRASG12D inhibition. sgRNAs targeting EGFR, PIK3CA, PTPN11, mTOR, and CDK2/4/6 were depleted in MRTX1133-treated (or vehicle-treated) cell lines or xenograft models, while hallmark tumor suppressor genes RB1, KEAP1, NF1 and PTEN were enriched. The enrichment of KEAP1 sgRNAs in PDAC models parallels findings with MRTX849 in preclinical models and is in line with emerging clinical data suggesting increased capacity to scavenge reactive oxygen species (ROS) may represent a mechanism of partial resistance to a non-covalent, non-electrophilic warhead-containing KRASG12D-selective inhibitor in PDAC. Treatment using small molecules targeting selected vulnerabilities in vitro and in vivo confirmed these genetic findings. Further evaluation of dependencies utilizing an integrated analysis of RNAseq data also revealed KRAS regulates and is critically dependent on pro-survival and cell cycle genes for cancer cell viability. These data lend further insight into tumor response to KRASG12D inhibition and provide key insight into the genes that mediate the mechanism of action of, as well as confer partial resistance to MRTX1133, and identify combination targets that can augment the anti-tumor effect of MRTX1133. Citation Format: Vickie Bowcut, Andrew Calinisan, David M. Briere, Lauren Hargis, Lars D. Engstrom, Jade Laguer, Darin Vanderpool, Xiaolun Wang, J David Lawson, Nicole Thomas, Robin Gunn, Christopher R. Smith, Julio Fernandez-Banet, Leo He, Adam Pavlicek, Lisa Rahbaek, Matthew A. Marx, Peter Olson, James G. Christensen, Jill Hallin. Pharmacogenomic insight into targetable vulnerabilities and modifiers of response to MRTX1133 in KRASG12D-mutant models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1131.