Abstract LB193: Chemical genomics identify novel druggable nodes and resistance pathways in the presence of concomitant SOS1 and KRAS inhibition
Authors: Khare Shilpi , Sudhakar Niranjan , Briere David M. , Yan Larry , Engstrom Lars D. , Laguer Jade , Medwid James , Vegar Laura , Vanderpool Darin , Marx Matthew A. , Ketcham John M. , Christensen James G. , Olson Peter , Haling Jacob R. 
Published: June 2022

Abstract
KRAS is the most frequently mutated oncogene in human cancer and facilitates uncontrolled growth through hyperactivation of the MAPK pathway. Recent data has consistently demonstrated co-dependencies of mutant-KRAS with extrinsic proteins that augment GTP-loading. Son of Sevenless homolog 1 (SOS1) is the most proximal of these proteins to KRAS and functions as a guanine nucleotide exchange factor (GEF) for the RAS subfamily of small GTPases, thus representing a highly sought-after druggable target. Utilizing a structure-based drug discovery approach, we identified a selective and potent SOS1 inhibitor, MRTX0902, that functions by disrupting the KRAS/SOS1 protein-protein interaction, ultimately preventing SOS1-mediated nucleotide exchange on KRAS. MRTX0902 enhances the anti-tumor activity of the KRASG12C inhibitor adagrasib across multiple KRASG12C-mutant preclinical models; however, it is anticipated that deeper pharmacological inhibition of KRAS signaling may give rise to novel combination targets and additional adaptive resistance mechanisms. To identify additional vulnerabilities and combination strategies, we conducted drug-anchored CRISPR screens in two KRASG12C xenograft models in the presence of MRTX0902 and adagrasib in vitro and in vivo. Interestingly, we found that the SOS1 homolog, SOS2, only emerges as a co-dependency under selective pressure of combination treatment and likely compensates for the inhibition of SOS1. Furthermore, multiple components from the PIK3CA/mTOR signaling pathway, PRMT5, and other non-vertical signal transduction pathways were uncovered and identified as genetic co-dependencies that emerged under selective pressure. Conversely, tumor suppressor genes including TSC1/2, PTEN, NF1, KEAP1 and TP53 along with phosphatases PTPN12 and PTPN14 enhanced tumor growth when knocked out providing a catalogue of putative resistance genes and mechanisms. Lastly, we utilized small molecule inhibitors of putative therapeutic targets identified from our CRISPR screens to validate genetic co-dependencies across in vitro and in vivo translational models. These studies uncover the potential utility of additional drug partners for the MRTX0902 and adagrasib combination and aide in the understanding of SOS and RAS biology in targeted cancer therapy.
Citation Format: Shilpi Khare, Niranjan Sudhakar, David M. Briere, Larry Yan, Lars D. Engstrom, Jade Laguer, James Medwid, Laura Vegar, Darin Vanderpool, Matthew A. Marx, John M. Ketcham, James G. Christensen, Peter Olson, Jacob R. Haling. Chemical genomics identify novel druggable nodes and resistance pathways in the presence of concomitant SOS1 and KRAS inhibition [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 LB193.