Abstract P214: MTAPnull-selective PRMT5 inhibitors drive regressions in MTAP-deleted xenograft models across histologies

Abstract

Abstract PRMT5 is a type II arginine methyltransferase that regulates essential cellular functions via symmetric dimethylation of target proteins involved in spliceosome regulation, cell cycle progression, apoptosis, the DNA-damage response, and other functions. PRMT5 dependence in cells with MTAP deletions is a strong and prevalent synthetic lethal interaction. Due to their mechanisms of action, existing clinical PRMT5 inhibitors do not recapitulate the selectivity for MTAPnull cells demonstrated by genetic perturbation. Given that MTAP deletion occurs in approximately 10-15% of all human cancer[i],[ii],[iii], a molecule that selectively kills MTAPnull cancer cells provides an important opportunity to deliver a targeted treatment to a significant patient population. We have discovered small molecules that exhibit MTA-cooperative PRMT5 binding and selectively kill MTAPnull cancer cells. Striking MTAP-dependent viability effects are demonstrated in MTAP-isogenic cell lines representing multiple lineages, and in a multi-lineage cell line panel comprised of 200 cancer cell lines. Furthermore, oral administration of an MTAPnull-selective PRMT5 inhibitor demonstrates dose-dependent antitumor activity and strong regressions across multiple histologies in both cancer cell line and patient-derived xenografts. These data suggest the therapeutic potential of MTAPnull-selective PRMT5 inhibitors in MTAP-deleted cancers. [i] Cerami et al., 2012 [ii] Gao et al., 2013 [iii] Lee et al., 2014 Citation Format: Kimberly J. Briggs, Kevin M. Cottrell, Matthew R. Tonini, Erik Wilker, Lina Gu, Charles B. Davis, Doug Whittington, Deepali Gotur, Haris Jahic, Matthew J. Goldstein, Alan Huang, John P. Maxwell. MTAPnull-selective PRMT5 inhibitors drive regressions in MTAP-deleted xenograft models across histologies [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P214.