IGF1R信号通路在非小细胞肺癌EGFR TKI耐药性产生中的作用及调控机制

EGFR TKI targeted therapy with gefitinib has achieved remarkable results in treating NSCLC patients. Primary or acquired resistance, EMT and lung cancer stem cells (CSCs) all contribute to resistance to EGFR TKI and are closely connected. Our studies have shown that IGF1R signaling pathway plays important roles in the regulation of resistance to EGFR TKI and EMT in lung cancer cells as well as of lung CSC stemness as CSC marker and could be potential target to overcome EGFR TKI resistance in NSCLC. To date, studies in this area have not been reported. By means of molecular biology, such as manipulation of gene and signaling pathway, cellular biology, such as isolation, identification and culture of lung CSCs, and transgenic mouse model, this grant is proposed to investigate the role of IGF1R signaling pathway in the regulation of resistance to EGFR TKI in NSCLC and underlying mechanisms, including primary and acquired resistance, EMT and lung CSC-mediated resistance; to investigate possible combined therapies with manipulation of IGF1R signaling pathway to overcome EGFR TKI resistance. Hopefully, knowledge we gain from this study of whole animals in vivo and cells in vitro could translate into new targeted therapies to overcome EGFR TKI resistance in NSCLC patients.

以吉非替尼为代表的EGFR TKI靶向治疗非小细胞肺癌效果显著，然而耐药性的产生是临床治疗失败的主要原因。耐药的肺癌细胞，上皮间质化的肺癌细胞和肺癌干细胞是导致耐药的根源，三者之间有着密切的联系。前期研究显示IGF1R信号通路通过调控肺癌细胞EGFR TKI耐药，肺癌细胞EMT以及作为肺癌干细胞表面分子标志物调控肺癌干细胞干性而成为克服耐药的潜在靶点；这方面的研究未见报道。本课题拟在此研究基础上，采用基因和信号通路调控等分子生物学、肺癌干细胞分离、鉴定和培养等细胞生物学方法以及可诱导肺癌转基因小鼠模型，研究IGF1R信号通路在非小细胞肺癌EGFR TKI耐药，包括原发和获得性耐药、EMT和肺癌干细胞介导的耐药中的作用和调控机制；探讨调控IGF1R信号通路的联合治疗方案克服EGFR TKI耐药。在细胞和整体动物层面上，为临床防治非小细胞肺癌 EGFR TKI耐药提供新的靶点和理论依据。

获得性耐药是非小细胞肺癌EGFR TKI靶向治疗的瓶颈。探讨获得性耐药的机制和寻找有效的可逆转耐药的靶点对肺癌的治疗具有十分重要的意义。肿瘤干细胞，上皮间质转化（EMT）和获得性耐药三者之间有着密切的联系。本课题探讨IGF1R信号通路在这三者中的作用和调控机制。研究发现：1. EGFR TKI获得性耐药的肺癌组织和肺癌细胞中存在EMT和肿瘤干细胞表型，同时整合素b3/IGF1R/NF-kB信号通路活性升高。2. 在细胞水平，抑制整合素b3/IGF1R/NF-kB信号通路能够部分逆转EGFR TKI获得性耐药和EMT表型以及抑制肺癌细胞干性。3. 在整体动物水平，抑制整合素b3/IGF1R/NF-kB信号通路能够抑制耐药肺癌的生长。本课题率先研究并发现整合素b3/IGF1R/NF-kB信号通路对非小细胞肺癌EGFR TKI获得性耐药，EMT和肿瘤细胞干性的调控作用，为临床克服EGFR TKI耐药提供新的靶点和理论依据。