Abstract LB-017: Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to marked dependence on PRMT5

Metabolic genes are increasingly recognized as targets of somatic genetic alteration in human cancer often leading to profound changes in intracellular metabolite concentrations. 5-Methylthioadenosine Phosphorylase (MTAP) is a key enzyme in the methionine salvage pathway that metabolizes methylthioadenosine (MTA) to adenine and methionine. Its chromosomal position proximal to CDKN2A results in frequent collateral homozygous deletion in a wide range of human cancers. By interrogating data from a large scale deep-coverage pooled shRNA screen across 390 cancer cell line models we found that the viability of MTAP null cancer cells is strongly impaired upon shRNA-mediated depletion of the protein arginine methyltransferase PRMT5. In MTAP deleted cells there is marked accumulation of the substrate MTA and surprisingly, we find that MTA is a specific inhibitor of the catalytic activity of PRMT5. In keeping with these data, knockout of MTAP in an MTAP-proficient cell line led to increased MTA levels and rendered them sensitive to PRMT5 depletion. Moreover, reconstitution of MTAP in an MTAP-deficient cell line fully rescued PRMT5 dependence. Collectively, these findings indicate that the collateral loss of MTAP in CDNK2A deleted cancers leads to accumulation of MTA that thereby creates a hypomorphic PRMT5 state that is selectively sensitized towards further PRMT5 inhibition. Citation Format: Konstantinos Mavrakis, E Robert McDonald III, Michael R. Schlabach, Eric Billy, Gregory R. Hoffman, Antoine deWeck, David A. Ruddy, Kavitha Venkatesan, Greg McAllister, Rosalie deBeaumont, Samuel Ho, Yue Liu, Yan Yan-Neale, Guizhi Yang, Fallon Lin, Hong Yin, Hui Gao, David Randal Kipp, Songping Zhao, Joshua T. McNamara, Elizabeth R. Sprague, Young Shin Cho, Justin Gu, Ken Crawford, Vladimir Capka, Kristen Hurov, Jeffrey A. Porter, John Tallarico, Craig Mickanin, Emma Lees, Raymond Pagliarini, Nicholas Keen, Tobias Schmelzle, Francesco Hofmann, Frank Stegmeier, William R. Sellers. Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to marked dependence on PRMT5. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-017.