靶向FAPα逆转非小细胞肺癌EGFR-TKI治疗耐受的作用及机制研究

针对EGFR突变的靶向治疗（EGFR-TKI）在非小细胞肺癌治疗中展现不可替代的作用，然而治疗耐受仍然是困扰临床的主要难题。FAPα是肿瘤相关成纤维细胞（CAFs）的特异性标志物。我们前期研究发现FAPα不仅在非小细胞肺癌EGFR-TKI耐药肿瘤间质中高表达，而且在耐药肿瘤组织实质和耐药细胞中亦高表达。采用磷酸化蛋白组学分析发现，FAPα通过活化PAK2介导非小细胞肺癌EGFR-TKI耐药。据此，本项目拟在前期工作的基础上，进一步阐明FAPα在EGFR-TKI耐药细胞上调表达的机制；解析FAPα促进EGFR-TKI耐药的作用及机制，阐明FAPα激活Rho/PAK2信号的分子机制；明确FAPα、PAK2表达与EGFR-TKI耐药的相关性及临床意义；评价靶向FAPα逆转EGFR-TKI耐药的可行性。本研究可为逆转非小细胞肺癌EGFR-TKI耐药提供新的靶点并开辟一条有实际应用价值的新策略。

EGFR-TKI targeted therapy has been playing an important role in treatment of non- small cell lung cancer (NSCLC), but almost unavoidable therapeutic resistance remains a major problem in successful treatment of NSCLC. FAPα is the specific marker of cancer-associated fibroblasts (CAFs). Our previous studies found that FAPα is high expressed in EGFR-TKI-resistant NSCLC tumor stroma, but also high expressed in EGFR-TKI-resistant NSCLC tumor parenchyma and EGFR-TKI-resistant NSCLC cells. Using phosphorylation proteomics analysis, we found that FAPα mediates EGFR-TKI resistance by activating PAK2. Therefore, our present proposal will clarify the regulation mechanisms of FAPα in EGFR-TKI-resistant NSCLC cells; systematically investigate the role and molecular mechanism of FAPα in promoting EGFR-TKI resistance, and clarify the regulation mechanisms of FAPα on Rho/PAK2 signaling; we will further investigate the pathological significance of FAPα and PAK2 in EGFR-TKI resistance, and seek the feasible strategy for targeting FAPα to reverse EGFR-TKI resistance. The research of this project can provide a new molecular target for reversing EGFR-TKI resistance in non-small cell lung cancer and develop a novel strategy with practical application value.