Abstract ND02: MRTX0902: A SOS1 inhibitor for therapeutic intervention of KRAS-driven cancers
Authors: Ketcham John M. , Khare Shilpi , Sudhakar Niranjan , Briere David M. , Yan Larry , Laguer Jade , Vegar Laura , Vanderpool Darin , Hallin Jill , Hargis Lauren , Bowcut Vickie , Lawson David , Gunn Robin J. , Ivetac Anthony , Thomas Nicole C. , Saechao Barbara , Nguyen Natalie , Clarine Jeffrey , Rahbaek Lisa , Smith Christopher R. , Burns Aaron C. , Marx Matthew A. , Christensen James G. , Olson Peter , Haling Jacob R. 
Published: June 2022

Abstract
KRAS is the most frequently mutated oncogene in cancer and drives uncontrolled growth through hyperactivation of the MAPK pathway. Significant progress has been made in the past several years to directly target KRASG12C with the FDA approval of sotorasib and the reported clinical activity of adagrasib (MRTX849). Despite these remarkable breakthroughs, additional therapies that enhance the depth and duration of response to KRASG12C inhibitors provide the opportunity to build upon the initial progress. SOS proteins are guanine nucleotide exchange factors (GEFs) that transduce receptor tyrosine kinase (RTK) signaling from the cell surface and facilitate the activation of RAS family proteins. In addition, SOS1 is a target of negative feedback signaling following RAS-mediated activation of the RAF-MEK-ERK cascade. Thus, SOS proteins represent a significant therapeutic node that maintains RAS pathway equilibrium as well as oncogenic signaling dynamics. Here we highlight the discovery and preclinical evaluation of MRTX0902, a potent, selective, and orally bioavailable inhibitor of SOS1 presently in IND-enabling studies. A structure-based approach was used to identify a novel chemical series that disrupts the protein-protein interaction between SOS1 and KRAS, thereby preventing SOS1-mediated GTP-exchange on GDP-bound KRAS. Considering MRTX849 preferentially binds to inactive GDP-bound KRASG12C, targeting SOS1 in this genetic context increases the ability of MRTX849 to bind and inhibit KRASG12C. The combination of MRTX0902 with MRTX849 enhances the depth and durability of an anti-tumor response when compared to MRTX849 alone in pre-clinical KRASG12C tumor models. MRTX0902 augments additional targeted therapies across a variety of RAS-addicted tumors, indicating that SOS1 inhibition is effective against a broad spectrum of mutations within the MAPK pathway. Furthermore, drug-anchored CRISPR experiments with MRTX0902 and MRTX849 uncovered a previously underappreciated functional role of the SOS1 paralog, SOS2, in KRAS-addicted tumors. In addition to aiding in the understanding of SOS and RAS family signaling dynamics, these studies implicate SOS2 as a potential cancer drug target in the context of SOS1/KRASG12C inhibition. In summary, we have used a structure-based approach to discover a SOS1 inhibitor that augments the anti-tumor activity of MRTX849 and additional targeted MAPK pathway inhibitors. We anticipate our findings to translate into the clinic and make an impact in patients with RAS-addicted tumors.
Citation Format: John M. Ketcham, Shilpi Khare, Niranjan Sudhakar, David M. Briere, Larry Yan, Jade Laguer, Laura Vegar, Darin Vanderpool, Jill Hallin, Lauren Hargis, Vickie Bowcut, David Lawson, Robin J. Gunn, Anthony Ivetac, Nicole C. Thomas, Barbara Saechao, Natalie Nguyen, Jeffrey Clarine, Lisa Rahbaek, Christopher R. Smith, Aaron C. Burns, Matthew A. Marx, James G. Christensen, Peter Olson, Jacob R. Haling. MRTX0902: A SOS1 inhibitor for therapeutic intervention of KRAS-driven cancers [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 ND02.