Abstract 2779: Identification of mechanism-based combination targets effective with the MTA-cooperative PRMT5 inhibitor MRTX1719 for the treatment of MTAP deleted cancers
Authors: Waters Laura , Aranda Ruth , Moya Krystal , Bowcut Victoria , Trinh David , Hebbert Allan , He Leo , Hover Laura D. , Fernandez-Banet Julio , Hallin Jill , Briere David M. , Christensen James G. , Olson Peter A. , Engstrom Lars D. 
Published: April 2023

Abstract
Previous studies identified PRMT5 as a synthetic lethal target for cancers harboring homozygous deletion of the MTAP gene (MTAP del) whereby accumulation of MTA, the MTAP substrate, partially inhibits PRMT5 activity leading to an increased dependency on PRMT5. MRTX1719 is an MTA cooperative PRMT5 inhibitor that preferentially binds to the PRMT5/MTA complex, leveraging the increased MTA concentration associated with MTAP deletion to selectively target MTAP del cancer cells while sparing normal tissues resulting in a broad therapeutic index. MTAP is adjacent to and co-deleted with the most commonly deleted tumor suppressor gene, CDKN2A, with significant prevalence in several indications of high unmet medical need including mesothelioma, cholangiocarcinoma, pancreatic, lung squamous, gastric, and esophageal cancers. MRTX1719 inhibited the growth of an extensive panel of MTAP del cell line-derived and patient-derived xenograft tumor models across various indications. MRTX1719-anchored CRISPR screens were performed with multiple models in vitro and in vivo and led to the identification of several rational and clinically feasible combination hypotheses. Subsequent, combination screening using a diverse set of small molecule inhibitors across a panel of cell line models was performed to validate combination targets, estimate synergism, and determine the effectiveness of selected MRTX1719 combinations. Prioritized strategies were tested in vivo where MRTX1719, in combination with agents inhibiting complementary mechanisms of action, demonstrated enhanced tumor growth inhibition compared to either agent alone, including but not limited to palbociclib (CDK4/6), olaparib (PARP), and Type I PRMT and Bcl-xL inhibitors. Further investigation into potential biomarkers conferring sensitivity or resistance to PRMT5 inhibition was also performed using orthogonal datasets including molecular characterization, differential expression, differential splicing and proteomic analysis. These data suggest MRTX1719, an MTA cooperative PRMT5 inhibitor currently in a Phase I clinical trial (NCT05245500), has the potential to be a synthetically lethal precision medicine for multiple indications harboring MTAP del with high unmet medical need either as a single agent or in combination with clinically feasible rational combination partners.
Citation Format: Laura Waters, Ruth Aranda, Krystal Moya, Victoria Bowcut, David Trinh, Allan Hebbert, Leo He, Laura D. Hover, Julio Fernandez-Banet, Jill Hallin, David M. Briere, James G. Christensen, Peter A. Olson, Lars D. Engstrom. Identification of mechanism-based combination targets effective with the MTA-cooperative PRMT5 inhibitor MRTX1719 for the treatment of MTAP deleted cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2779.