The novel PRMT5-substrate adaptor interface provides a therapeutic target in MTAP null tumors

项目摘要 胰腺癌是世界上最致命的癌症之一。只有不到7%的患者存活 这种致命的疾病。尽管努力，但有效的治疗方法很少。有趣的是，甲基转移酶PRMT 5具有 在MTAP无效肿瘤中被鉴定为癌症依赖性，MTAP无效肿瘤占所有肿瘤的15%和所有肿瘤的30%。 胰腺导管腺癌因此，PRMT 5是胰腺癌中有吸引力的靶点。这个PRMT 5 依赖性是由于与频繁缺失的MTAP基因相邻的MTAP基因的乘客缺失而产生的。 9号染色体上的肿瘤抑制基因CDKN 2A。在缺乏MTAP的肿瘤中，其底物甲硫腺苷 (MTA)积累并竞争性抑制PRMT 5酶。虽然PRMT 5的治疗靶向具有 专注于靶向催化口袋，我们的初步研究表明，一种新的和潜在的重要 PRMT 5甲基化体的表面，其可以克服PRMT 5催化的细胞特异性和功效问题。 抑制剂的因此，我假设新确定的PRMT 5-底物适配器接口是用于 PRMT 5活性，因此是MTAP无效肿瘤生长所必需的。通过以下两个目标，我们 将说明PRMT 5-底物接头位点是否是所有或特定PRMT 5功能所需的， 确定这种蛋白质相互作用位点的破坏是否可能在胰腺癌中具有治疗益处。

Project Abstract Pancreatic cancer is one of the most lethal types of cancer worldwide. Less than 7% of patients survive this deadly disease. Despite efforts, few effective therapies exist. Intriguingly, the methyltransferase PRMT5 has been identified as a cancer dependency in MTAP null tumors, which constitute 15% of all tumors and 30% of pancreatic ductal adenocarcinomas. Therefore, PRMT5 is an attractive target in pancreatic cancer. This PRMT5 dependency arises due to the passenger deletion of the MTAP gene that is adjacent to the frequently deleted tumor suppressor gene CDKN2A on chromosome 9. In tumors lacking MTAP, its substrate, methylthioadenosine (MTA) accumulates and competitively inhibits the PRMT5 enzyme.!While therapeutic targeting of PRMT5 has focused on targeting the catalytic pocket, our preliminary studies demonstrate a novel and potentially important face of the PRMT5 methylosome that may overcome cellular specificity and efficacy issues with PRMT5 catalytic inhibitors. Therefore, I hypothesize that the newly identified PRMT5-substrate adaptor interface is required for PRMT5 activity and is thus essential for the growth of MTAP null tumors. Through the following two Aims, we will address whether the PRMT5-substrate adaptor site is required for all or particular PRMT5 functions and establish whether disruption of this protein interaction site might have a therapeutic benefit in pancreatic cancer.