Abstract 4228: PRISM cancer cell viability profiling enables insights into clinical candidate target selectivity: A case study revealing the most selective PRMT5 inhibitors for cancers with MTAP loss

Abstract PRISM is a highly multiplexed, genomic barcode-based cell line viability technology of nearly 1000 solid tumor and hematopoietic cell lines, which enables profiling of cellular responses to small molecules or biologics to discover biomarkers of sensitivity and resistance and generate mechanistic hypotheses. In addition to the genomic characterization of PRISM cell lines, we have generated large pharmacologic perturbation reference datasets such as the ever-growing PRISM Oncology Reference dataset, in which hundreds of clinical stage agents are systematically profiled for cell viability effects. To highlight the capability of PRISM to uncover novel insights regarding agent selectivity, here we describe the results of profiling seven unique protein arginine methyltransferase 5 (PRMT5) targeting agents (six inhibitors and one degrader). PRMT5 is a methyl transferase capable of methylating arginines on histones and non-histone protein substrates involved in important cellular processes such as growth and migration. Homozygous deletions of the PRMT5 regulator, methylthioadenosine phosphorylase (MTAP) occur in 10% of all cancers, including 40% of glioblastomas, 25% of pancreatic adenocarcinomas, and 15% of NSCLCs. Loss of MTAP leads to accumulation of methylthioadenosine (MTA) and partial inhibition of PRMT5, creating a potential therapeutic window for further inhibition of PRMT5. Our results reveal that the MTA-cooperative PRMT5 targeting agents are more selective for this target patient population (cancers with MTAP loss) compared to earlier classes of PRMT5 inhibitors. Additionally, our results suggest the PRMT5 degrader we tested does have on-target activity, but its effectiveness may be dampened by MDR1-mediated efflux. Taken together, these results showcase the capabilities of the PRISM assay to characterize clinical candidates for selectivity within the patient population of interest and uncover potential liabilities (such as drug transporter efflux). Citation Format: Laura Doherty, Colleen Harrington, Mustafa Kocak, Anthony Fazio, John Davis, Emily Reeves, Rachael Barry, Claudine Mapa, Dennie Frederick, Alvin Kalathungal, Jillian Eskra, Tenzin Sangpo, Melissa Ronan, William Sellers, Matthew Rees, Jennifer Roth. PRISM cancer cell viability profiling enables insights into clinical candidate target selectivity: A case study revealing the most selective PRMT5 inhibitors for cancers with MTAP loss [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4228.