美国Agios制药公司Katya Marjon团队发现，MAT2A抑制通过减少依赖PRMT5的mRNA剪接并诱导DNA损伤来阻止MTAP缺失癌细胞的生长。这一研究成果于2021年1月14日在线发表在国际学术期刊《癌细胞》上。

据研究人员介绍，甲基硫代腺苷磷酸化酶（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，在所有癌症中约有15％与CDKN2A共缺失。这种共同缺失导致侵袭性肿瘤的预后不良，并缺乏有效的分子靶向疗法。代谢酶蛋氨酸腺苷基转移酶2α（MAT2A）被鉴定为MTAP缺失癌症中的合成致死靶标。

研究人员报道了对MAT2A有效抑制剂的表征，该抑制剂可大幅降低S-腺苷甲硫氨酸（SAM）的水平，并证明在MTAP缺失的癌细胞和肿瘤中具有抗增殖活性。通过使用RNA测序和蛋白质组学，研究人员证明MAT2A抑制机制与减少的蛋白质精氨酸甲基转移酶5（PRMT5）活性和剪接扰动有关。研究人员进一步显示，HCT116 MTAP^-/-细胞中的MAT2A抑制会导致DNA损伤和有丝分裂缺陷，这些发现为MAT2A临床候选分子AG-270与抗有丝分裂紫杉烷类药物联合使用提供了理论依据。

附：英文原文

Title: MAT2A inhibition blocks the growth of MTAP-deleted cancer cells by reducing PRMT5-dependent mRNA splicing and inducing DNA damage

Author: Peter Kalev, Marc L. Hyer, Stefan Gross, Zenon Konteatis, Chi-Chao Chen, Mark Fletcher, Max Lein, Elia Aguado-Fraile, Victoria Frank, Amelia Barnett, Everton Mandley, Joshua Goldford, Yue Chen, Katie Sellers, Sebastian Hayes, Kate Lizotte, Phong Quang, Yesim Tuncay, Michelle Clasquin, Rachel Peters, Jaclyn Weier, Eric Simone, Joshua Murtie, Wei Liu, Raj Nagaraja, Lenny Dang, Zhihua Sui, Scott A. Biller, Jeremy Travins, Kevin M. Marks, Katya Marjon

Issue&Volume: 2021-01-14

Abstract: 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 tumorswith poor prognosis that lack effective, molecularly targeted therapies. The metabolicenzyme methionine adenosyltransferase 2α (MAT2A) was identified as a synthetic lethaltarget in MTAP-deleted cancers. We report the characterization of potent MAT2A inhibitors that substantiallyreduce levels of S-adenosylmethionine (SAM) and demonstrate antiproliferative activity in MTAP-deleted cancer cells and tumors. Using RNA sequencing and proteomics, we demonstratethat MAT2A inhibition is mechanistically linked to reduced protein arginine methyltransferase5 (PRMT5) activity and splicing perturbations. We further show that DNA damage andmitotic defects ensue upon MAT2A inhibition in HCT116 MTAP/ cells, providing a rationale for combining the MAT2A clinical candidate AG-270 withantimitotic taxanes.

DOI: 10.1016/j.ccell.2020.12.010

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30658-9