Abstract 4636: Genome-wide drug anchor screens identify CAAP1 and AKAP17A as regulators of PRMT5 inhibitor sensitivity

Abstract

Abstract MTA-cooperative PRMT5 inhibitors are an emerging treatment option for patients with one of the 10-15% of all human cancers harboring MTAP homozygous deletion. To identify potential regulators of sensitivity to PRMT5 inhibitors, we performed genome-wide CRISPR knockout screens in the presence and absence of an MTA-cooperative PRMT5 inhibitor. Knockout of CAAP1 and AKAP17A were among the strongest sensitizing hits across multiple MTAP-deleted cancer cell lines representing different histologies. Strikingly, the CAAP1 gene co-localizes with MTAP and CDKN2A on chromosome 9p21. Co-deletion of CAAP1 is reported in 20 percent of MTAP-deleted cancers in the TCGA PanCancer Atlas. CAAP1 or AKAP17A knockout in MTAP-deleted cancer cell lines sensitized the cells to PRMT5 inhibitors including the clinical stage MTA-cooperative inhibitors, TNG908 and TNG462, and the non-MTA-cooperative inhibitor, GSK3326595. Moreover, we discovered that CAAP1 and AKAP17A protein levels are interdependent, as knockout of either gene caused decreased protein levels for the other. Consistent with this finding, CAAP1 reconstitution in CAAP1-deleted cell lines led to increased AKAP17A levels. Endogenous CAAP1 and AKAP17A protein levels are positively correlated across a panel of cancer cell lines and MTAP-deleted patient-derived xenograft models. Consistent with a previous report (Ni et al., 2023), exogenous CAAP1 and AKAP17A co-immunoprecipitation studies suggest that the proteins form a protein complex. AKAP17A and CAAP1 are not well-characterized proteins, but PRMT5 inhibitors induce global alternative splicing events (ASEs) in cancer cells, and based on preliminary studies a possible function for the CAAP1/AKAP17A complex could be to mitigate ASEs induced by PRMT5 inhibition. Collectively, these data indicate that CAAP1 and AKAP17A exist interdependently and mediate sensitivity to PRMT5 inhibitors. The colocalization and 20 percent incidence of CAAP1 deletion in the setting of MTAP deletion may suggest that such patients will have improved responses to PRMT5-targeted therapy. S. Yoda and M. R. Tonini contributed equally. Citation Format: Satoshi Yoda, Matthew R. Tonini, Hilary E. Nicolson, Samuel Poleretzky, Silvia Fenoglio, Steven Lombardo, Lauren Grove, Samuel R. Meier, Ashley Choi, Yi Yu, Kevin M. Cottrell, John P. Maxwell, Teng, Jannik N. Andersen, Kimberly J. Briggs. Genome-wide drug anchor screens identify CAAP1 and AKAP17A as regulators of PRMT5 inhibitor sensitivity [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(6_Suppl):Abstract nr 4636.