MAT2A抑制劑透過減少依賴PRMT5的mRNA剪接和誘導DNA損傷來阻斷MTAP缺失的癌細胞的生長

MAT2A inhibition blocks the growth of MTAP-deleted cancer cells by reducing PRMT5-dependent mRNA splicing and inducing DNA damage(Cancer Cell, IF:26.602)

Kalev Peter,Hyer Marc L,Gross Stefan et al. MAT2A inhibition blocks the growth of MTAP-deleted cancer cells by reducing PRMT5-dependent mRNA splicing and inducing DNA damage.[J] .Cancer Cell, 2021, undefined: undefined.

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）基因位於週期蛋白依賴性激酶抑制劑2A （CDKN2A）腫瘤抑制基因附近，並在大約15%的所有癌症中與CDKN2A共同刪除。這種共缺失導致惡性腫瘤的預後差，缺乏有效的分子靶向治療。代謝酶甲硫氨酸腺苷轉移酶2α（MAT2A）被鑑定為mtap缺失的癌症的合成致死靶點。我們報道了有效的MAT2A抑制劑的特性，它可以顯著降低s -腺苷蛋氨酸（SAM）的水平，並在mtap缺失的癌細胞和腫瘤中顯示抗增殖活性。透過RNA測序和蛋白質組學，我們證明了MAT2A抑制機制與降低的蛋白精氨酸甲基轉移酶5 （PRMT5）活性和剪接干擾有關。進一步研究表明，在HCT116 MTAP細胞中，MAT2A抑制會導致DNA損傷和有絲分裂缺陷，這為MAT2A臨床候選抗原AG-270與抗有絲分裂紫杉類化合物的結合提供了理論依據。