The methylthioadenosine phosphorylase (MTAP) gene is located adjacent to the cyclin-dependent kinase inhibitor 2A (CDKN2A) tumor-suppressor gene and is co-deleted with CDKN2A in approximately 15% of all cancers. This co-deletion leads to aggressive tumors with poor prognosis that lack effective, molecularly targeted therapies. The metabolic enzyme methionine adenosyltransferase 2α (MAT2A) was identified as a synthetic lethal target in MTAP-deleted cancers. We report the characterization of potent MAT2A inhibitors that substantially reduce levels of S-adenosylmethionine (SAM) and demonstrate antiproliferative activity in MTAP-deleted cancer cells and tumors. Using RNA sequencing and proteomics, we demonstrate that MAT2A inhibition is mechanistically linked to reduced protein arginine methyltransferase 5 (PRMT5) activity and splicing perturbations. We further show that DNA damage and mitotic defects ensue upon MAT2A inhibition in HCT116 MTAP^−/− cells, providing a rationale for combining the MAT2A clinical candidate AG-270 with antimitotic taxanes.

甲硫腺苷磷酸化酶 ( MTAP ) 基因位于细胞周期蛋白依赖性激酶抑制剂 2A ( CDKN2A ) 肿瘤抑制基因附近，并且在大约 15% 的所有癌症中与CDKN2A共同缺失。这种共同缺失导致侵袭性肿瘤预后不良，缺乏有效的分子靶向治疗。代谢酶蛋氨酸腺苷转移酶 2α (MAT2A) 被确定为MTAP缺失癌症的合成致死靶点。我们报告了有效的 MAT2A 抑制剂的特性，该抑制剂可显着降低S-腺苷甲硫氨酸 (SAM) 的水平，并在MTAP缺失的癌细胞和肿瘤中表现出抗增殖活性。通过 RNA 测序和蛋白质组学，我们证明 MAT2A 抑制在机制上与蛋白质精氨酸甲基转移酶 5 (PRMT5) 活性降低和剪接扰动有关。我们进一步表明，在 HCT116 MTAP ^−/−细胞中抑制 MAT2A 后会出现 DNA 损伤和有丝分裂缺陷，这为将 MAT2A 临床候选药物 AG-270 与抗有丝分裂紫杉烷相结合提供了理论依据。