Abstract 1644: Dual inhibition of MAT2A and PRMT5 delivers synergistic anti-tumor responses in preclinical models of MTAP-deleted cancer
Authors: Fischer Marcus M. , Gerrick Kimberline , Belmontes Brian , Slemmons Katherine , Freyman Yevgeniy , Jain Jay , Federowicz Steve , Bishof Isaac , Rao Arjun A. , Fleury Melissa , Mounir Zineb , Lackner Mark R. , Hughes Paul E. , White Mike , Neilan Claire L. 
Published: April 2023

Abstract
Approximately 15% of all tumors harbor deletions in the 9p21 locus that encompass CDKN2A and MTAP. MTAP fuels the adenine and methionine salvage pathways by converting MTA into precursors of building blocks for protein and DNA production. In MTAP-deleted (MTAPdel) tumors, cellular MTA accumulates and partially inhibits the essential protein methyl transferase, PRMT5, through direct displacement of the cofactor S-adenosyl methionine (SAM) from the PRMT5 active site. This context provides therapeutic opportunities, currently under clinical evaluation, to selectively extinguish PRMT5 activity in tumor cells with MAT2A inhibitors that limit SAM synthesis or with direct PRMT5 inhibitors that are MTA-cooperative. Preclinical modeling of these synthetic lethal relationships, and elucidation of their cellular mechanisms of action, suggests efficacy can vary depending upon the extent of MTA accumulation and/or adaptive compensation to PRMT5 inhibition. To potentially maximize therapeutic activity among mechanistically heterogenous MTAPdel tumors, we evaluated combinatorial pathway suppression with MAT2A and PRMT5 inhibitors in MTAPWT and MTAPdel tumor models in vitro and in vivo. We noted synergistic antiproliferative effects when the potent and selective MAT2A inhibitor IDE397 was combined with any of multiple MTA-cooperative PRMT5 inhibitors in MTAPdel cell lines that exhibit sensitivity to each single agent. In vivo, the combination of IDE397 and MTA-cooperative PRMT5 inhibitors were well tolerated, and induced durable tumor regressions, including complete responses, at dose levels well below the maximally efficacious preclinical dose of each individual agent in MTAPdel lung adenocarcinoma and pancreas cancer models H838 and BXPC3. Pharmacodynamic target engagement in the tumor was evaluated by quantitative assessment of symmetric dimethyl arginine (SDMA), as detected by IHC, and indicated earlier onset and greater extent of PRMT5 inhibition by combination treatment as compared to either agent alone. The potentiation of the antitumor response with the combination did not occur in the MTAPWT setting. Thus, combined inhibition of MAT2A and PRMT5 potentially offers a compelling dual synthetic lethal opportunity to address unmet need for the many patients afflicted with MTAPdel cancers.
Citation Format: Marcus M. Fischer, Kimberline Gerrick, Brian Belmontes, Katherine Slemmons, Yevgeniy Freyman, Jay Jain, Steve Federowicz, Isaac Bishof, Arjun A. Rao, Melissa Fleury, Zineb Mounir, Mark R. Lackner, Paul E. Hughes, Mike White, Claire L. Neilan. Dual inhibition of MAT2A and PRMT5 delivers synergistic anti-tumor responses in preclinical models of MTAP-deleted cancer [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 1644.