FoxF1/整合素αvβ3正反馈环路介导非小细胞肺癌EGFR-TKI继发耐药的机制研究

The acquired resistance to EGFR-TKI is one of the most important reasons for the targeted therapy failure in NSCLC. Integrin αvβ3 acts as a critical adhesion molecule which is closely related with the tumor stemness and drug resistance. Our recent study found that the expression level of integrin αvβ3 became upregulated during the process of acquired resistance of NSCLC to EGFR-TKI, and integrin αvβ3 might induce the cancer stemness of NSCLC by forming positive feedback loop with FoxF1 through an anchorage-independent pathway. Based on the current results and related research , we speculated that FoxF1/αvβ3 positive feedback loop, which was facilitated by Hedgehog and other signaling pathways, could mediate the acquired resistance of NSCLC to EGFR-TKI through induction of cancer stemness. This study is a continuation and further research of our preliminary work. To test our hypothesis, clinical specimens, cell experiments and animal models were processed in this study to explore the role and underlying mechanism of FoxF1/αvβ3 positive feedback loop in the induction of resistance to EGFR-TKI in NSCLC, so as to provide valuable rationale and theory for the targeted therapy of NSCLC.

非小细胞肺癌（NSCLC）对EGFR-TKI继发耐药的产生是其分子靶向治疗失败的主要原因，而整合素αvβ3是与肿瘤干性和耐药密切相关的关键黏附分子。我们近期研究发现EGFR-TKI继发耐药过程能够显著诱导NSCLC细胞中整合素αvβ3的表达，而且整合素αvβ3可能通过非锚定依赖性途径与FoxF1形成正反馈环路，诱导肿瘤干性的形成。综合前期研究结果我们推测，在Hedgehog通路和其它信号通路的协助下，整合素αvβ3与FoxF1形成FoxF1/整合素αvβ3正反馈环路，从而诱导NSCLC的肿瘤干性，促进EGFR-TKI继发耐药过程。本研究是前期工作的深化和延续，拟采用临床标本、细胞实验与动物模型等多层次实验，围绕FoxF1/整合素αvβ3这一正反馈环路，明确整合素αvβ3促进NSCLC发生EGFR-TKI继发性耐药的具体分子机制，从而为NSCLC的靶向治疗提供有价值的实验基础和理论依据。

非小细胞肺癌（NSCLC）对EGFR-TKI继发耐药的产生是其分子靶向治疗失败的主要原因，而整合素αvβ3是与肿瘤干性和耐药密切相关的关键黏附分子。本课题发现，EGFR-TKI继发耐药过程能够通过诱导和分选两个途径提高NSCLC细胞整合素αvβ3的表达水平。整合素αvβ3能够通过非锚定依赖性途径与Hedgehog通路关键成员FoxF1形成正反馈环路，促进克隆增殖和自我更新能力，诱导肿瘤干性及EGFR-TKI继发耐药。.随着整合素β3抑制剂治疗癌症的III期临床试验的失败，整合素β3特异性抑制剂的开发一直处于低迷状态。本课题发现EGFR-TKI继发耐药后NSCLC组织中整合素β3和AXL的表达显著增加。同样，整合素β3和AXL在EGFR-TKI继发耐药NSCLC细胞株中的表达明显高于亲本细胞株。敲低整合素β3不仅可以削弱EGFR-TKI耐药的NSCLC细胞对EGFR-TKI的耐药性，还可以降低AXL和胞核YAP的水平。NSCLC亲本细胞过表达整合素β3后，细胞对EGFR-TKI的耐药性增强，AXL和胞核YAP的表达增加。通过基因或药物抑制YAP通路可以有效地逆转整合素β3过表达对AXL表达的诱导，而激活YAP通路可以挽救整合素β3敲低对AXL表达的抑制。AXL抑制剂可以抑制整合素β3介导的 EGFR-TKI 耐药、集落形成和上皮间质转化。.本研究是前期工作的深化和延续，通过探索新的下游靶点，明确了FoxF1/整合素αvβ3正反馈环路在EGFR-TKI 耐药中的重要作用，揭示了整合素αvβ3通过YAP通路上调AXL促进EGFR-TKI继发耐药的分子机制。本课题提示整合素αvβ3表达阳性的晚期NSCLC患者可能会从EGFR-TKI与AXL抑制剂联合治疗中获益，为NSCLC的精准靶向治疗提供有价值的实验基础和理论依据。