MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells.
MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells.
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DOI：
10.1126/science.aad5214
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发表时间：
2016-03-11
期刊：
影响因子：
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通讯作者：
Garraway LA
中科院分区：
文献类型：
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作者：
Kryukov GV;Wilson FH;Ruth JR;Paulk J;Tsherniak A;Marlow SE;Vazquez F;Weir BA;Fitzgerald ME;Tanaka M;Bielski CM;Scott JM;Dennis C;Cowley GS;Boehm JS;Root DE;Golub TR;Clish CB;Bradner JE;Hahn WC;Garraway LA
癌症依赖性的发现有可能为治疗策略提供信息并识别推定的药物靶点。综合来自癌细胞系的全面基因组分析和癌细胞依赖性的功能表征的数据，我们发现，甲硫腺苷磷酸化酶（MTAP）的损失赋予了对蛋白质精氨酸甲基转移酶5（PRMT 5）及其结合伴侣WDR 77的选择性依赖。MTAP由于其与通常缺失的肿瘤抑制基因CDKN 2A接近而经常丢失。我们观察到在MTAP缺失的细胞中甲硫腺苷（MTA; MTAP裂解的代谢物）的细胞内浓度增加。此外，MTA特异性抑制PRMT 5酶活性。MTA或小分子PRMT 5抑制剂的施用显示与表达同基因MTAP的对应物相比，MTAP无效癌细胞系的细胞活力的适度优先损害。总之，我们的研究结果揭示了PRMT 5作为一个潜在的脆弱性，通过一个共同的“乘客”基因组改变增强了多个癌症谱系。
The discovery of cancer dependencies has the potential to inform therapeutic strategies and to identify putative drug targets. Integrating data from comprehensive genomic profiling of cancer cell lines and from functional characterization of cancer cell dependencies, we discovered that loss of the enzyme methylthioadenosine phosphorylase (MTAP) confers a selective dependence on protein arginine methyltransferase 5 (PRMT5) and its binding partner WDR77. MTAP is frequently lost due to its proximity to the commonly deleted tumor suppressor gene, CDKN2A. We observed increased intracellular concentrations of methylthioadenosine (MTA; the metabolite cleaved by MTAP) in cells harboring MTAP deletions. Furthermore, MTA specifically inhibited PRMT5 enzymatic activity. Administration of either MTA or a small molecule PRMT5 inhibitor showed a modest preferential impairment of cell viability for MTAP-null cancer cell lines compared to isogenic MTAP-expressing counterparts. Together, our findings reveal PRMT5 as a potential vulnerability across multiple cancer lineages augmented by a common “passenger” genomic alteration.