Huang Jun, Yu Qiuhua, Zhou Yanjuan, Chu Ying, Jiang Feng, Zhu Xiaobo, Zhang Junjie, Wang Qiang
Department of Thoracic-Cardiology, Wujin Hospital Affiliated with Jiangsu University, The Wujin Clinical College of Xuzhou Medical University, Changzhou 213017, China.
Department of Respiratory, Wujin Hospital Affiliated with Jiangsu University, The Wujin Clinical College of Xuzhou Medical University, Changzhou 213017, China.
Transl Cancer Res. 2020 Feb;9(2):1044-1052. doi: 10.21037/tcr.2019.12.60.
The study was aimed to investigate the mechanisms causing acquired chemoresistance to icotinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), in non-small cell lung cancer (NSCLC).
Three wildtype NSCLC cell lines were used to produce icotinib-resistant (IR) cell lines. Real-time PCR and western blot assays were used to detect the mRNA and protein levels of nerve growth factor receptor (NGFR) and forkhead box P3 (FOXP3). MTT assay was used to detect the viability of cells. Luciferase activity and chromatin immunoprecipitation (ChIP) assays were used to detect the transactivation activity of FOXP3.
NGFR and FOXP3 were dramatically increased in three IR NSCLC cell lines, and both proteins were required for induction of icotinib resistance. NGFR-induced icotinib resistance was partially related to activation of AKT, a well-known chemoresistance inducer in many tumor types. Activated AKT could induce the expression of FOXP3 which further induce icotinib through transactivating NGFR expression by binding to its promoter. In addition, the inducing of FOXP3 could also induce icotinib resistance solely.
NGFR, AKT and FOXP3 form a positive feedback loop, by which the abilities of NGFR and FOXP3 on inducing icotinib resistance are further enhanced. We believe that NGFR and FOXP3 might be novel therapeutic targets in NSCLC.
本研究旨在探讨非小细胞肺癌（NSCLC）中导致对表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）埃克替尼产生获得性化疗耐药的机制。
使用三种野生型NSCLC细胞系构建埃克替尼耐药（IR）细胞系。采用实时PCR和蛋白质印迹分析检测神经生长因子受体（NGFR）和叉头框P3（FOXP3）的mRNA和蛋白质水平。采用MTT法检测细胞活力。采用荧光素酶活性和染色质免疫沉淀（ChIP）分析检测FOXP3的反式激活活性。
三种IR NSCLC细胞系中NGFR和FOXP3显著升高，这两种蛋白均是诱导埃克替尼耐药所必需的。NGFR诱导的埃克替尼耐药部分与AKT激活有关，AKT是许多肿瘤类型中一种众所周知的化疗耐药诱导因子。激活的AKT可诱导FOXP3表达，FOXP3通过与NGFR启动子结合反式激活其表达，进而进一步诱导埃克替尼耐药。此外，FOXP3的诱导也可单独诱导埃克替尼耐药。
NGFR、AKT和FOXP3形成一个正反馈环，通过该正反馈环，NGFR和FOXP3诱导埃克替尼耐药的能力进一步增强。我们认为，NGFR和FOXP3可能是NSCLC新的治疗靶点。
