Discovery of Enhanced Dependency on the Enzyme PRMT5 in Cancer Cells Bearing Deletion of MTAP.MTAP, located on 9p21 adjacent to the CDKN2A/CDKN2B locus, which is commonly deleted in cancer, encodes a critical metabolic enzyme that cleaves MTA to generate precursor substrates for methionine and adenine salvage pathways. Interestingly, PRMT5 is inhibited by MTA (due to the fact that MTA acts as a competitive inhibitor of SAM which is required for PRMT5 function) and is therefore partially inhibited in tumors lacking MTAP. Because PRMT5 is essential for cell survival, cells lacking MTAP are especially sensitive to pharmacologic inhibition of PRMT5. MTA, methylthioadenosine; MTAP, methylthioadenosine phosphorylase; MTR-1-P, methylthioribose-1-phosphate; PRMT5, protein arginine methyltransferase 5; SAM, s-adenosyl methionine.