PIK3R1基因cSH2结构域突变促进子宫内膜癌进展的机制研究

PIK3R1是编码PI3K通路调节亚基p85α蛋白的基因，在多种癌症中存在高频突变，在子宫内膜癌病人中突变频率高达40%。重要的是，携带PIK3R1突变的病人的生存率显著低于野生型病人。cSH2结构域是p85α高频发生突变的位点，但尚未有研究鉴别并解析cSH2结构域上的驱动突变。申请人前期研究提示，cSH2结构域存在高频驱动突变，这些突变可能通过调控p110的不同亚基激活PI3K通路，进而促进细胞的恶性转化。本项目旨在通过基因组学、细胞生物学、分子生化、药物敏感性等实验方法，鉴别cSH2结构域具有促癌作用的驱动突变，深入探究这些驱动突变异常调控p110亚基介导的分子机制，并通过体内外实验验证突变细胞对p110抑制剂的药物敏感性。该项目研究结果有望优化子宫内膜癌病人的靶向治疗方案，为治疗携带PIK3R1基因cSH2结构域驱动突变的肿瘤病人提供新的思路。

PIK3R1 encodes p85α, the regulatory subunit of class IA phosphatidylinositol 3-kinase (PI3K) pathway. PIK3R1 gene mutations are frequently observed in multiple cancer lineages, and over 40% of endometrial cancer patients bring PIK3R1 mutations. Strikingly, cancer patients with PIK3R1 mutations were found to have a remarkably low survival chance than wild-type ones. A cluster of patient-derived hotspot mutations are occurred at cSH2 domain, yet its driver mutations have not been fully identified and characterized in any cancer types. Our preliminary data have shown that some of the mutations at cSH2 domain are driver mutations, and these mutations could activate PI3K signals by modulating p110 isoforms. Significantly, these driver mutations render the cells more sensitive to p110 specific inhibitors. By integrative analyses of functional genomics, molecular biology, and pharmacological approaches, this project aims to 1) identify the driver mutations that frequently occurred at cSH2 domain of PIK3R1, 2) explore the underlying oncogenic mechanisms induced by driver mutation, and 3) determine the sensitivities of driver mutations to the p110 isoform-specific inhibitors. Functional characterizations of PIK3R1 cSH2 domain driver mutations and associated treatment susceptibility may provide mechanism-based therapeutic options for cancer patients who carrying these mutations.