非经典NOTCH1通路的耐药调控与靶向抑制

肿瘤耐药是肿瘤复发的重要原因，如何消除耐药，是当前临床治疗上的关键问题之一。前期工作中，我们建立了完整的体外和体内临床肺肿瘤研究体系，并且首次发现，尽管NOTCH1受体通过下游HES1蛋白调控肺肿瘤干细胞的自我更新，但却通过与HES1无关的非经典通路来调控肺肿瘤干细胞的铂类耐药。为了进一步研究NOTCH受体的耐药调控及其靶向抑制，我们期望在前期建立的研究体系和成果基础上，深入开展以下几方面研究：1）揭示NOTCH1非经典耐药通路；2）筛选新颖小分子化合物，特异性地靶向NOTCH1下游耐药通路；3）发展新颖联合用药策略，采用NOTCH1耐药通路抑制剂结合各种临床肿瘤治疗。通过开展这个项目，我们期望解析NOTCH1的非经典耐药通路，研发新颖的NOTCH1耐药机制的靶向抑制剂，优化联合治疗策略。

Therapeutic resistance often results in tumor relapse, leading to clinical mortality. One of the clinical challenges is how to decode resistance mechanisms and target them for therapies. We have found that NOTCH1 maintains self-renewal of lung cancer stem-like cells (LCSCs) in clinical tumors via canonical HES1 pathway. Intriguingly, NOTCH1 induces cisplatin resistance via HES1-independent non-canonical mechanism(s). Based on our previous study and findings, we propose to study NOTCH-induced therapeutic resistance with following aims: 1) to decode the non-canonical NOTCH1 signaling for resistance; 2) to screen for small molecule compounds targeting NOTCH1-induced resistance; 3) to develop combinatorial therapies to resensitize resistant tumor cells and eliminate them with current clinical therapies. We hope our proposed project will provide a novel insight of NOTCH1-mediated therapeutic resistance and establish rational ways to treat resistant tumors in clinics in the future.