MAT2A Inhibition Blocks the Growth of MTAP-Deleted Cancer Cells by Reducing PRMT5-Dependent mRNA Splicing and Inducing DNA Damage
MAT2A Inhibition Blocks the Growth of MTAP-Deleted Cancer Cells by Reducing PRMT5-Dependent mRNA Splicing and Inducing DNA Damage
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DOI：
10.1016/j.ccell.2020.12.010
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发表时间：
2021-02-08
期刊：
影响因子：
50.3
通讯作者：
Marjon, Katya
中科院分区：
文献类型：
--
作者：
Kalev, Peter;Hyer, Marc L.;Marjon, Katya
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（CDKN 2A）肿瘤抑制基因附近，并且在大约15%的癌症中与CDKN 2A共缺失。这种共缺失导致预后不良的侵袭性肿瘤，缺乏有效的分子靶向治疗。代谢酶甲硫氨酸腺苷转移酶2 α（MAT 2A）被鉴定为MTAP缺失癌症中的合成致死靶标。我们报告了有效的MAT 2A抑制剂的表征，该抑制剂可显著降低S-腺苷甲硫氨酸（SAM）的水平，并在MTAP缺失的癌细胞和肿瘤中表现出抗增殖活性。使用RNA测序和蛋白质组学，我们证明MAT 2A抑制机制与蛋白质精氨酸甲基转移酶5（PRMT 5）活性降低和剪接干扰有关。我们进一步表明，在HCT 116 MTAP（-/-）细胞中MAT 2A抑制后，DNA损伤和有丝分裂缺陷随之发生，为MAT 2A临床候选物AG-270与抗有丝分裂紫杉烷类化合物的组合提供了理论基础。
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 2 alpha (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.