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靶向PIK3R1基因nSH2结构域驱动突变的功能性研究

批准号81703066 学科分类肿瘤生物治疗 ( H1611 )
项目负责人张慧婷 负责人职称副研究员 依托单位香港大学深圳研究院
资助金额22.00
万元
项目类别青年科学基金项目 研究期限2018 年 01 月 01 日 至
2020 年 12 月 31 日
中文主题词癌症基因组学;分子靶向治疗;磷脂酰肌醇3-激酶;驱动突变;药物基因组学
英文主题词Cancer genomics;Targeted therapy;PI3K;Driver mutation;Pharmacogenomics

摘要

中文摘要 靶向治疗是指靶向癌症进展中特异性分子的治疗方案,是癌症治疗革命性的策略。 近些年癌症基因组学的发展加速了以基因组为基础的精准医疗的进展。癌基因异常会对下游通路产生功能性影响,改变癌细胞对特异性药物的反应,同时可作为临床的生物靶标。PIK3R1基因编码PI3K通路的调节亚基p85α,在多种肿瘤中存在高频率的突变。在PI3K通路中,p85α通过与催化亚基p110结合形成异源二聚体,稳定p110的表达且抑制其活性。nSH2结构域是PIK3R1基因频发突变的热点结构域,在脑癌、子宫内膜癌、乳腺癌、结肠癌、前列腺癌、肺癌等多种肿瘤中均可检测到该结构域的突变。因此,探究突变的机制及发展针对这些突变的有效治疗手段具有重要的临床意义。通过癌症组学的综合分析、分子生物学、结构生物学以及药物基因组学等方法,我们将重点研究nSH2结构域突变在肿瘤形成、下游通路以及药物敏感性等方面的作用。我们的研究结果将促进癌症
英文摘要 Targeted therapy, which interferes with specific molecules required for tumorigenesis, has proven useful and revolutionized cancer treatment. Targeted therapy could improve antitumor efficacy while reducing side effects. The recent advances in cancer genomics have accelerated the development of genome-informed precision cancer medicine. Accumulating evidence has shown that genomic aberrations in cancer genes can have functional impact on downstream signaling and thereby alter the responses to specific drugs. These genetic aberrations can be biomarkers to guide clinical decision. ..The PIK3R1 gene, which encodes for the p85α regulatory subunit of the phosphatidylinositol 3-kinase (PI3K) pathway, is frequently aberrated across tumor lineages. The canonical action of p85α is to inhibit the activity but also the degradation of the p110 catalytic subunit by forming heterodimer with p110. Recent research findings from our group have demonstrated the functional effects of PIK3R1 mutations on signaling pathway activation and sensitivity to targeted therapeutics. Our findings revealed loss-of-function mutants that are unable to inhibit p110α catalytic activity. Secondly, we are the first to demonstrate how p85α homodimer stabilizes PTEN protein and PIK3R1 mutants that disrupt p85α homodimer formation, leading to PTEN destabilization and PI3K pathway activation. Apart from the canonical involvement in the PI3K pathway, a subset of PIK3R1 mutations unexpectedly activates the MAPK pathway and renders cells sensitive to MAPK pathway inhibitors that are not predicted by the known functions of p85α. These findings underscore the importance to functionally characterize mutations of a target cancer gene to identify the right therapy and to avoid unmatched therapeutic strategy. ..A cluster of PIK3R1 hotspot mutations occurs at the nSH2 domains. Importantly, the cancer types with these hotspot mutations are diverse, including cancers of brain, endometrium, breast, colon, prostate and gastric, etc. Therefore, research on novel therapeutics is of high significance to improve the survival of this large group of patients. However, functional characterization of these mutations on downstream signaling and drug sensitivity has not been investigated in any cancer types. This proposal aims to unravel the functional impact and therapeutic implication of PIK3R1 nSH2 domain mutations in cancer. Through integrative analyses of cancer omics, molecular biology, structural biology and cancer therapeutics, the effects of these mutations on tumorigenicity, downstream signaling and drug sensitivity in cancer will be addressed. The research findings will provide insight for the development of therapeutic strategies that can be delivered to cancer patients with the PIK3R1 nSH2 domain driver mutations.
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