基于PI3K抑制剂激活STAT5研究CML对BEZ235耐受的分子机制及解决方案

PI3K pathway activation due to aberrant upstream signaling or mutation of pathway components occurs in more cancers than any other cellular signaling pathway. This has driven interest in developing inhibitors targeting the PI3K into cancer drug armamentarium. However, to date, responses of tumors to monotherapy have been modest and accompanied by rapid emergence of drug resistance. Rational combination therapies will partially overcome or prevent emergence of resistance. Indeed, combination strategies based on PI3K inhibitor are beginning to fulfill the initial excitement in breast cancer and other solid tumors, however, lack in leukemia. This project aims for finding synergistic therapeutic strategies, based on PI3K inhibitor, in chronic myeloid leukemia (CML). In previously work, we found that PI3Ki induced apoptosis in CML is not obvious, and discovered phosphorylation STAT5 at Tyr694 is up-regulated accompanied with inhibition of PI3K. Therefore, this project intends to screen moleculars, which could regulate activation of STAT5 induced by BEZ235, through construction of shRNA cell lines targeting molecules including kinases, transcription factors and translation initiation factors. Study the mechanisms of STAT5 activation induced by BEZ235, could help us in understanding of the mechanisms of CML tolerance to BEZ235. We expect to screen targets which have synergistic effect combining with BEZ235 in the apoptosis induction of CML. The expected results of this study may deepen our understanding the mechanism of CML tolerance to PI3K inhibitors，which could provide important tips for CML treatment.

靶向PI3K的抑制剂 (PI3Ki) 一直是抗肿瘤药物的研究热点，然而PI3K单靶点抑制剂往往治疗效果一般且易产生耐药。多靶点的协同治疗是解决单靶点耐药的重要手段，而与乳腺癌、胰腺癌等实体瘤相比，靶向PI3K在血液肿瘤中的协同治疗研究相对缺乏。本课题选择慢性髓细胞白血病 (CML) 为模型，寻找基于PI3Ki的协同治疗策略。申请人前期工作证实，PI3Ki BEZ235诱导CML细胞凋亡的作用不明显，且首次发现BEZ235会引起STAT5活化增强。申请人将通过构建一系列肿瘤信号分子shRNA细胞系的方法，筛选在BEZ235引起STAT5活化中发挥关键作用的分子，研究CML对BEZ235耐受的机制。并从上述分子中寻找可以协助PI3Ki诱导CML细胞凋亡的靶分子，探究该靶点与PI3Ki的协同治疗策略。本课题的预期结果可以加深对CML耐受PI3Ki机制的理解，并为CML治疗提供重要提示。

靶向PI3K的抑制剂 (PI3Ki) 是抗肿瘤药物的研究热点，而PI3K单靶点抑制剂治疗效果一般且易产生耐药。本课题以慢性髓细胞白血病 (CML) 为模型，通过研究CML对BEZ235低敏感的分子机制，寻找基于PI3Ki的协同治疗策略。申请人通过PI3Ki处理CML，筛选PI3Ki促进STAT5活化增强的分子，寻找可与PI3K发挥协同作用的靶点分子。通过激活STAT5 分子的单靶点抑制、及与PI3Ki抑制剂同步抑制，研究筛选到靶点诱导CML凋亡的协同效果，并阐述其协同机制。结果证实，PI3Ki BEZ235诱导可引起集落刺激因子受体（CSF-R）表达上调，进而导致p-STAT5tyr694活化增强。STAT5的活化进一步增强JAK2/STAT5/PIM信号通路的活化，使得CML对BEZ235低敏感。而单独的抑制PIM抑制剂并不能有效诱导CML细胞凋亡，但PIM与PI3Ki制剂协同抑制后，CML细胞凋亡增多，且协同抑制后，K562裸鼠皮下肿瘤形成实验的疗效明显优于单靶点抑制。并发现PI3Ki与PIMi的协同治疗机制为两者均可使（真核翻译起始因子4B，eIF4B ）Ser422位发生磷酸化。本课题的预期结果可以加深对CML耐受PI3Ki机制的理解，并为CML耐药后的协同治疗提供重要提示。

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