Abstract 1637: MAT2A inhibition in MTAP-/- tumors confers mechanistic vulnerabilities to multiple clinically actionable synthetic lethal drug combinations

Abstract

Abstract Methylthioadenosine phosphorylase (MTAP) is co-deleted with the tumor suppressor CDKN2A in approximately 15% of solid tumors and can elicit dependency on methionine adenosyltransferase 2A (MAT2A) production of S-adenosyl methionine (SAM), the major methyl donor for cellular methyltransferase reactions. IDE397, a potent small molecule inhibitor of MAT2A, was developed to exploit this synthetic lethal relationship for therapeutic benefit in patients harboring MTAP-/- cancers and demonstrates selective anti-tumor activity in MTAP-/- models. Evaluation of IDE397 efficacy across a panel of 48 MTAP-/- PDX models revealed consistent tumor growth inhibition (TGI>60%) across diverse lineages, with distinct enrichment of tumor regressions in squamous lung cancers. To further enhance the efficacy of IDE397 within and among tumor lineages, we sought to identify rational combination partners. A three-pronged approach was employed that dovetailed molecular profiling of IDE397 drug effects in vivo, chemogenomic evaluation of selective drug sensitivities in MTAP-/- cell lines across the CCLE, and high-throughput in vitro drug combination screens. Unbiased pathway analysis of IDE397-dependent changes in MTAP-/- PDX transcriptomes revealed perturbations in pre-mRNA splicing, DNA damage repair, and mitotic spindle assembly as commonly enriched across diverse models. Evaluation of altered pre-mRNA splicing patterns suggested that many of these changes may be a consequence of selective impairment of PRMT5-dependent support of spliceosome activity. Notably, sensitivities to drugs that inhibit the fidelity of pre-mRNA splicing, genome stability, and microtubule stability were enriched in MTAP-/- cell lines, suggesting that the biological processes selectively altered by IDE397 in tumors are already partially impaired by MTAP deletion. Finally, an IDE397 in vitro drug combination viability screen of over 400 drugs returned taxanes, platins, topoisomerase inhibitors, splicing inhibitors, and anti-folates as selectively synergistic with IDE397 in MTAP-/- models. Synergy between IDE397 and pemetrexed was of particular interest given mechanistic convergence of the methionine salvage and folate cycle pathways on nucleotide synthesis in the context of MTAP-/-. Accordingly, this combination provided enhanced tumor growth inhibition in vivo in MTAP-/- NSCLC and bladder models and is currently under evaluation in phase 1. Collectively, these observations indicate that MAT2A inhibition can generate cell states in MTAP-/- tumor cells that are selectively vulnerable to approved chemotherapies and targeted therapies. These synergistic relationships may provide a predictive biomarker strategy for multiple IDE397 synthetic lethal combination therapies. Citation Format: Kimberline Y. Gerrick, Jenny Laraio, Kelsey Annen, Hoang Tran, Marcus M. Fischer, Yevgeniy Freyman, Geeta Sharma, Isaac Bishof, Stephen Federowicz, Divya Pankajakshan, Claire L. Neilan, Biju Mangatt, Anthony Mazurek, Mark R. Lackner, Michael White, Zineb Mounir. MAT2A inhibition in MTAP-/- tumors confers mechanistic vulnerabilities to multiple clinically actionable synthetic lethal drug combinations [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 1637.