Abstract 4631: Evaluation of the impact of homozygous MTAP truncations on the activity and selectivity of MTA-cooperative PRMT5 inhibitors

Abstract Homozygous deletion of the MTAP gene occurs in 10-15% of all human cancers. To benefit this large and diverse patient population, MTA-cooperative PRMT5 inhibitors, including TNG908 and TNG462, have been developed to leverage the synthetic lethal relationship between MTAP deletion and PRMT5 inhibition. MTA-cooperative PRMT5 inhibitors selectively bind the PRMT5-MTA complex driving selective inhibition of PRMT5 in MTAP-deleted cancers while sparing normal, MTAP-proficient cells. Our PRMT5 inhibitors are currently in Phase I/II clinical trials (NCT05275478 and NCT05732831), and eligibility is restricted to patients with tumors with confirmed MTAP loss either detected by next-generation sequencing (NGS) or immunohistochemistry. MTAP gene loss occurs in cancers because of its chromosomal proximity to one of the most common genetically altered tumor suppressor genes, CDKN2A, but the chromosomal 9p breakpoints for the co-deletion are not uniform. Indeed, while clinical NGS testing and preclinical data confirm that homozygous intragenic MTAP breakpoints occur, the functional consequence of any given breakpoint on MTAP enzymatic activity and protein function remains unknown. Given the potential implications for homozygous intragenic MTAP deletions to impact the clinical response to MTA-cooperative PRMT5 inhibitors, we have started to evaluate the loss-of-function phenotype of various MTAP truncations to determine whether they retain MTAP activity. Here, we present our initial functional genomics analysis of this important diagnostic biomarker using in vitro cDNA reconstitution approaches for MTAP activity combined with analysis of PRMT5 inhibitor sensitivity. Ultimately, these data may help refine patient enrollment on clinical trials to drive the maximum benefit for patients with MTAP-deleted cancers. Citation Format: Matthew R. Tonini, Andre A. Mignault, Douglas A. Whittington, Steven A. Lombardo, Binzhang Shen, Hannah Stowe, Satoshi Yoda, Shangtao Liu, Minjie Zhang, Kevin M. Cottrell, Samuel R. Meier, Heidi Rego, Jennifer Morawiak, Ellen Hooper, Yi Yu, Heather DiBenedetto, Adam S. Crystal, Teng, Kimberly Briggs. Evaluation of the impact of homozygous MTAP truncations on the activity and selectivity of MTA-cooperative PRMT5 inhibitors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4631.