肿瘤微环境是影响肺癌EGFR-TKI耐药的重要因素。内源性生物电场是肿瘤微环境重要组成部分，但其是否影响TKI耐药尚不明确。我们在前一个国家自然科学基金研究生物电调控肺癌侵袭的过程中发现：①肺癌细胞移植瘤表面存在内源性生物电场，且TKI耐药细胞移植瘤表面电场强度显著大于敏感细胞移植瘤；②生物电上调TKI敏感肺癌细胞抗凋亡能力，诱导EMT，减弱TKI杀伤作用；③电刺激上调微囊蛋白Caveolin-1（Cav-1）表达，增强其活化。有研究表明，整合素（integrin）与细胞应答生物电信号有关，且β3-integrin/NF-kB通路参与调控TKI耐药。整合素的表达、分布及转运均接受Cav-1调控。据此推测，生物电可能通过活化Cav-1/β3-integrin通路，引起肺癌EMT及TKI耐药。本项目旨在明确肺癌应答生物电发生TKI耐药的关键分子机制，为解决肺癌TKI耐药难题提供理论基础与思路。

Tumor microenvironment(TME) plays an important role in regulation of EGFR-TKI resistance in lung cancer. Endogenous bio-electric fields (EFs) is an important component of TME, while little is known about its influence on TKI resistance. Supported by the previous NSFC, we have conducted research on electrical control of lung cancer invasion and directional migration. We have found: ① Endogenous EFs existed on the surface of lung cancer xenografts, and the EF magnitude on xenografts of TKI-resistant cells is larger than that of the TKI-sensitive cells; ② EF stimulation upregulated the anti-apoptotic ability of TKI-sensitive lung cancer cells, induced EMT, and decreased TKI-induced apoptosis; ③ EF stimulation increased expression of Caveolin-1 and phosphoralyted Caveolin-1 in TKI-sensitive lung cancer cells. Previously, it was reported that integrin played a role in sensing EFs, while β3-integrin/NF-kB pathway was involved in TKI resistance. Caveolin-1 was able to modulate integrin expression, distribution and trafficing. Thus, we speculate that bio-EFs may control EGFR-TKI resistance through activation of β3-integrin/NF-kB pathway and EMT. The current project aims to find out the key mechanism of electrical control of TKI resistance, thus providing new approaches to solve the problem of EGFR-TKI resistance in lung cancer.