非小细胞肺癌EGFR-TKI继发性耐药机制复杂，目前仍是基础及临床研究难题。课题组利用表达谱基因芯片检测发现泛素-蛋白酶体系统（UPS）中的26S蛋白酶体亚基PSMC2在TKI耐药的肺癌组织和细胞中表达显著升高，同时UPS活性增强且自噬效应减弱；特异性抑制TKI耐药细胞株中PSMC2的表达后，UPS活性降低，自噬效应增强，细胞株的耐药性被逆转。由此我们提出假说：PSMC2可能通过UPS调控自噬效应导致EGFR-TKI继发性耐药。课题组拟采用基因转染、qPCR、western blot和激光共聚焦显微镜等方法，在分子、细胞、动物水平上分析PSMC2、UPS与自噬效应在TKI耐药中的交互作用，并用临床标本加以验证，明确PSMC2通过UPS调控自噬效应在非小细胞肺癌EGFR-TKI耐药形成中的作用和机制，为寻找有效逆转耐药的靶点和个体化治疗提供新思路。

The mechanisms of acquired EGFR-TKI resistance is complicated and remain as key problems in basic and clinical research of nonsmall-cell lung cancer (NSCLC). Our previous results showed that expression of 26S proteasome subunit PSMC2 in UPS was elevated significantly in both cell lines and clinical samples with EGFR-TKI resistance by gene expression profile microarray, companioned with activation of UPS as well as autophagy downregulation. Decreased UPS activation, increased autophagy and reversed drug resistance was found after inhibition of PSMC2 expression. We hypothesized that PSMC2 may be involved in the EGFR-TKI resistance by modulating autophagy through UPS. Therefore, the present project intends to use gene transfection, real-time PCR, western blot and laser confocal microscope etc. to explore the cross-actions among PSMC2, UPS and autophagy in EGFR-TKI resistance in vitro and vivo, and further confirm the actions in clinical samples. The clarifying of the mechanisms that PSMC2 involved in EGFR-TKI acquired resistance may provide new thoughts in targets on drug resistance reverse and personalized treatment.