Abstract B098: Unbiased in vitro and in vivo drug anchor screens identify mechanisms of resistance and sensitization for MTA-cooperative PRMT5 inhibitors in MTAP-deleted cancer models

Abstract

Abstract Homozygous deletion of the MTAP gene is one of the most common genetic alterations in cancer, affecting 10-15% of all human cancer. Clinical MTA-cooperative PRMT5 inhibitors, including TNG908 and TNG462, were developed to leverage the well-characterized synthetic lethal interaction between PRMT5 inhibition and MTAP deletion. Indeed, the first disclosed clinical data for an MTA-cooperative PRMT5 inhibitor demonstrated the ability of TNG908 to selectively inhibit PRMT5 in MTAP-deleted tumors while sparing adjacent normal, MTAP-proficient cells in patients. To further explore the mechanism of action of MTA-cooperative PRMT5 inhibitors in MTAP-deleted cells, we employed multiple CRISPR-based editing platforms (CRISPRn, CRISPRi and CRISPRa) to conduct unbiased MTA-cooperative PRMT5 inhibitor anchor screens in vitro and in vivo. A panel of cancer models representing multiple histologies revealed potential PRMT5 inhibitor sensitization and resistance pathways that also include mechanisms that are specific to MTA-cooperative inhibitors. Specifically, the results of these screens identify 1) the effect of MTA/SAM metabolism on MTA-cooperative PRMT5 inhibitors, and 2) identification of potential sub-stratification strategies for patients with MTAP-deleted cancer, and 3) the activity of PRMT5 in anti-apoptotic pathways and synergy between PRMT5 and BCLxL inhibition. Citation Format: Steven Lombardo, Matthew R Tonini, Lauren Grove, Silvia Fenoglio, James Tepper, Binzhang Shen, Hannah Stowe, Shangtao Liu, Samuel R Meier, Ashley H Choi, Tenzing Khendu, Yi Yu, Kevin M Cottrell, John P Maxwell, Jannik N Andersen, Alan Huang, Kimberly J Briggs, Teng Teng. Unbiased in vitro and in vivo drug anchor screens identify mechanisms of resistance and sensitization for MTA-cooperative PRMT5 inhibitors in MTAP-deleted cancer models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B098.