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。不到7%的患者存活下来 这种致命的疾病。尽管做出了努力，但有效的疗法寥寥无几。有趣的是，甲基转移酶PRMT5 被确定为MTAP阴性肿瘤的癌症依赖者，占所有肿瘤的15%和30% 胰腺导管腺癌。因此，PRMT5是治疗胰腺癌的一个有吸引力的靶点。本PRMT5 由于乘客缺失与频繁缺失的MTAP相邻的MTAP基因而产生依赖性 9号染色体上的肿瘤抑制基因CDKN2A。在缺乏MTAP的肿瘤中，其底物甲硫代腺苷 (MTA)积累并竞争性抑制PRMT5酶。而PRMT5的治疗靶向 聚焦于催化口袋，我们的初步研究展示了一个新的和潜在的重要 可以克服PRMT5催化的细胞特异性和有效性问题的PRMT5羟基体的表面 抑制剂。因此，我假设新发现的PRMT5-底物适配器接口是 因此，PRMT5活性对MTAP阴性肿瘤的生长是必不可少的。通过以下两个目标，我们 将解决所有或特定PRMT5功能是否需要PRMT5底物适配器位置以及 确定破坏这一蛋白质相互作用位点是否可能对胰腺癌有治疗益处。

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.