MAT2A Inhibition Blocks the Growth of MTAP-Deleted Cancer Cells by Reducing PRMT5-Dependent mRNA Splicing and Inducing DNA Damage

The methylthioadenosine phosphorylase (MTAP) gene is situated next to the cyclin-dependent kinase inhibitor 2A (CDKN2A) tumor-suppressor gene and it is co-deleted with CDKN2A in roughly 15% of cancers. This co-deletion results in aggressive tumors with poor prognosis that lack effective, molecularly targeted therapies. The metabolic enzyme methionine adenosyltransferase 2a (MAT2A) was recognized as an artificial lethal target in MTAP-deleted cancers. We report the portrayal of potent MAT2A inhibitors that substantially reduce amounts of S-adenosylmethionine (Mike) and demonstrate antiproliferative activity in MTAP-deleted cancer cells and tumors. Using RNA sequencing and proteomics, we show MAT2A inhibition is mechanistically associated with reduced protein arginine methyltransferase 5 (PRMT5) activity and splicing perturbations. We further reveal that DNA damage and mitotic defects ensue upon MAT2A inhibition in HCT116 MTAP-/- cells, supplying a rationale for mixing the MAT2A clinical candidate AG-270 with antimitotic taxanes.