Anti-tumor Activity of the Type I PRMT Inhibitor, GSK3368715, Synergizes with PRMT5 Inhibition through MTAP Loss

Andrew Fedoriw, Satyajit R Rajapurkar, Shane O'Brien, Sarah V Gerhart, Lorna H Mitchell, Nicholas D Adams, Nathalie Rioux, Trupti Lingaraj, Scott A Ribich, Melissa B Pappalardi, Niyant Shah, Jenny Laraio, Yan Liu, Michael Butticello, Chris L Carpenter, Caretha Creasy, Susan Korenchuk, Michael T McCabe, Charles F McHugh, Raman Nagarajan, Craig Wagner, Francesca Zappacosta, Roland Annan, Nestor O Concha, Roberta A Thomas, Timothy K Hart, Jesse J Smith, Robert A Copeland, Mikel P Moyer, John Campbell, Kim Stickland, James Mills, Suzanne Jacques-O'Hagan, Christina Allain, Danielle Johnston, Alejandra Raimondi, Margaret Porter Scott, Nigel Waters, Kerren Swinger, Ann Boriack-Sjodin, Tom Riera, Gideon Shapiro, Richard Chesworth, Rabinder K Prinjha, Ryan G Kruger, Olena Barbash, Helai P Mohammad
Cancer Cell 2019 July 8, 36 (1): 100-114.e25
Type I protein arginine methyltransferases (PRMTs) catalyze asymmetric dimethylation of arginines on proteins. Type I PRMTs and their substrates have been implicated in human cancers, suggesting inhibition of type I PRMTs may offer a therapeutic approach for oncology. The current report describes GSK3368715 (EPZ019997), a potent, reversible type I PRMT inhibitor with anti-tumor effects in human cancer models. Inhibition of PRMT5, the predominant type II PRMT, produces synergistic cancer cell growth inhibition when combined with GSK3368715. Interestingly, deletion of the methylthioadenosine phosphorylase gene (MTAP) results in accumulation of the metabolite 2-methylthioadenosine, an endogenous inhibitor of PRMT5, and correlates with sensitivity to GSK3368715 in cell lines. These data provide rationale to explore MTAP status as a biomarker strategy for patient selection.

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