EGFR-TKI耐药是限制其疗效和临床应用的瓶颈。近来研究表明，BIM多态性和低表达是TKI耐药的重要原因，HDACi可以克服BIM多态性逆转耐药，但对BIM野生型及MCL-1等抗凋亡蛋白高表达的肺癌作用有限。我们前期工作发现，经典降糖药Metformin可逆转TKI耐药，并能显著上调BIM野生型TKI耐药细胞中的BIM的表达，抑制MCL-1等抗凋亡蛋白。因此，Metformin和HDACi可能具有协同调控BIM通路及凋亡的作用，二者协同可能克服多种耐药机制所致TKI耐药。本项目拟研究Metformin协同HDACi对多种机制所致TKI耐药肺癌细胞的作用，进一步探讨TKI耐药的分子机制及逆转策略，有望证实Metformin和HDACi通过调控BIM信号通路克服原发及继发TKI耐药的协同作用，为临床提供较广泛适用的克服TKI耐药的联合用药方案，具有重要科学意义。

Drug resistance is the key problem that restricts the clinical use of Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs). Recent study shows that BIM deletion polymorphism and low expression play important roles in TKI resistance. Histone deacetylase inhibitors (HDACi) could overcome TKI resistance through BIM upregulation in lung cancer cells with BIM deletion polymorphism, while it has little effect in BIM-wild type lung cancer cells, or cells with high expression of anti-apoptotic proteins including BCL-2 and MCL-1. Our reseach indicated that a standard anti-diabetic drug, metformin, could significantly overcome TKI resistance. Surprisingly, metformin was found to increase BIM expression in a number of lung cancer cells, including TKI sensitive cells and TKI resistant cells due to T790M mutation, K-RAS mutation, C-Met amplification, or EMT. Moveover, metformin can inhibit expression of MCL-1 and BCL-2. Thus, metformin and HDACi may cooperately target BIM signaling pathway, and the combination may overcome TKI resistance of multiple mechanisms. The current research aims to study the effect and mechanisms of metformin in combination with HDACi on TKI resistance. Hopefully we will prove the complementary synergy of co-treatment with metformin and HDACi on TKI sensitivity, thus providing a new approach which may be generally adoptted to treat NSCLC patients with EGFR mutations.