Biology, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
Pharmacology, Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
Cancer Cell. 2021 Feb 8;39(2):209-224.e11. doi: 10.1016/j.ccell.2020.12.010. Epub 2021 Jan 14.
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.
甲基硫腺苷磷酸化酶（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，大约 15%的所有癌症中与 CDKN2A 同时缺失。这种共缺失导致预后不良的侵袭性肿瘤，缺乏有效的、针对分子靶点的治疗方法。代谢酶蛋氨酸腺苷转移酶 2α（MAT2A）被鉴定为 MTAP 缺失癌症的合成致死靶点。我们报告了强效 MAT2A 抑制剂的特征，这些抑制剂可显著降低 S-腺苷甲硫氨酸（SAM）的水平，并在 MTAP 缺失的癌细胞和肿瘤中显示出抗增殖活性。通过 RNA 测序和蛋白质组学，我们证明 MAT2A 抑制与精氨酸甲基转移酶 5（PRMT5）活性降低和剪接扰动在机制上相关。我们进一步表明，在 HCT116 MTAP 细胞中抑制 MAT2A 后会导致 DNA 损伤和有丝分裂缺陷，为将 MAT2A 临床候选药物 AG-270 与抗有丝分裂紫杉醇联合使用提供了依据。
