肺癌是致死率最高的恶性肿瘤，揭示靶向治疗下肺癌细胞程序性死亡的调控机制是解决耐药和抵抗复发的关键。以往研究初步建立了靶向用药与肿瘤细胞凋亡的关系，但对用药过程中程序性死亡的动态调控缺乏深入探索。我们系统研究凋亡通路，意外发现BLC-2家族抗凋亡蛋白MCL1随着靶向药物作用显著升高，敲除MCL1或联用MCL1抑制剂加速细胞凋亡和焦亡，从而增强药物疗效；这一表型源于分子药物抑制能够上调BIM，BIM适应性结合并稳定MCL1蛋白，其过程可能由PI3K/mTOR负反馈信号通路调控。本课题将在前期预实验的基础上，进一步阐明肺癌在靶向药物作用下适应性稳定MCL1蛋白的分子机制，系统探讨消除对MCL1保护从而控制肺癌的治疗策略。这些研究将揭示适应性稳定MCL1蛋白作为一种新的靶向药物抵抗机制，指导联合用药在肺癌治疗中的开发和应用。

Lung cancer represents the most life-threatening human malignancy. Although patient prognosis has been significantly improved by recent application of molecular targeted therapies, drug resistance and tumor recurrence remain the major hurdle for further increase survival rate. We have focused on the potential role of programmed cell death in targeted therapies. Our preliminary data indicated that MCL1, a vital member of the anti-apoptotic BCL-2 family proteins, displayed an elevated expression along with drug treatment. The feedback activation of PI3K/mTOR pathway was likely the underlying mechanism of this adaptive drug resistance. MCL1 depletion using CRISPR-Cas9 or its pharmaceutical inhibition markedly facilitated cell apoptosis and pyroptosis, and as a result, promoted the efficacy of targeted agents. Based on these findings, we propose this project to expand our understanding on the biological function of MCL1 in therapeutic resistance. We will further investigate the molecular mechanisms of MCL1 upregulation during drug treatment, and explicitly define the downstream effector events of co-targeting driver-mutations and MCL1 in lung cancer. These studies will establish feedback activation of MCL1 as a novel molecular mechanism of adaptive drug resistance, and provide a conceptual rationale for exploiting MCL1 inhibitors as a new therapeutic opportunity to treat lung cancer patients undergoing targeted therapies.