靶向PI3K抗肿瘤药物耐药机制的研究

PI3Kδ and PI3Kα have been validated as important anticancer targets. PI3K isoform-specific inhibitors are promising next generation anticancer drugs with more specificity and lower toixicity. The chance for human tumors to develop resistance including intrisic and aquired resistance to PI3K isoform-selective inhibitors is quite high due to their high spesificity. Therefore, it is of great significance to perform perspective study on the mechanism of drug resistance, which will be helpful to circumvent resistacne and improve the efficacy of cancer therapy with PI3K isoform-specific inhibitors. In this study, the mechanism of resistance to anti-cancer drugs targeting PI3K δ/ α will be systematically studied with our newly obtained PI3Kδ inhibitor X-370 and PI3Kα inhibitor CYH33, including study on the intrinsic resistance, in which biomarkers capable of preddicting the sensitivity/resistance to drugs will be explored in the aim of identify patients that will be most likely to be benefitted from trerapy targeting PI3K δ/ α; study on the aquired resistance as well as study on combinatorial use of drugs based on the mechanism of drug resistance. This study will not only elucidate the selectivity of PI3K δ/ α among human tumors and shed new light on the personalized drug therapy in the clinic， but also will provide useful clues for discovery new inhibitors or strategy of combinatorial drug therapy.

PI3Kδ和PI3Kα已被确证为重要的抗肿瘤靶点。PI3K亚型选择性抑制剂有可能成为特异性更高、毒副作用更低的新一代抗肿瘤药物。由于其特异性高，产生原发性和获得性耐药的几率极高，、进行前瞻性药物耐受机制研究，对于克服耐药提高疗效具有重要意义。本课题拟以前期得到的PI3Kδ抑制剂X-370和PI3Kα抑制剂CYH33为研究对象，深入系统研究靶向PI3Kα/δ抗肿瘤药物的耐药机制，包括:原发性耐药机制机制的研究，探寻能够预测药物耐受/敏感的标志物，发现可能对靶向PI3Kα或PI3Kδ治疗耐受/敏感的人群；获得性耐药机制机制的研究以及基于耐药机制的联合用药研究。本课题的实施不仅将阐明PI3Kα/δ抑制剂抗肿瘤效应的选择性，为临床上个体化用药提供理论依据；还将发现其获得性耐药产生的机制，为开发新型抑制剂或探寻联合用药策略提供线索。

PI3Kδ和PI3Kα已被确证为重要的抗肿瘤靶点。PI3K 亚型选择性抑制剂有可能成为特异性更高、毒副作用更低的新一代抗肿瘤药物。由于其特异性高，产生原发性和获得性耐药的几率极高，进行前瞻性药物耐受机制研究，对于克服耐药提高疗效具有重要意义。本课题按照任务书的内容，以前期得到的PI3Kδ抑制剂X-370 和PI3Kα抑制剂CYH33 为研究对象，深入系统研究靶向PI3Kα/δ抗肿瘤药物的耐药机制，包括:原发性耐药机制的研究，探寻能够预测药物耐受/敏感的标志物，发现可能对靶向PI3Kα或PI3Kδ治疗耐受/敏感的人群；获得性耐药机制机制的研究以及基于耐药机制的联合用药研究。通过本项目的实施，发现Erk磷酸化受PI3Kδ调控的B淋巴型白血病细胞对X-370敏感，发现乳腺癌细胞酪氨酸激酶表达谱决定乳腺癌对PIK3K抑制剂的敏感性,通过构建对CYH33耐受的细胞株，对其获得性耐受机制进行了探索，发现PI3Kα抑制剂与CDK4/6抑制剂对kRAS突变肺癌具有协同抑制作用，推动完成了CYH33的临床前研究并获得临床研究批件。.通过本项目的实施，发表通讯作者SCI研究论文7篇，应邀Acta Pharmacol Sin撰写PI3K亚型选择性抑制剂研究进展，在Medicinal Research Reviews发表PI3Kδ选择性抑制剂研究进展，获得中国专利授权2项，国际专利授权3项。2名研究骨干晋升为副研究员，培养硕士研究生毕业2名，博士研究生毕业3名。