Background
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).
Conclusions
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.
Methods
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.
Results
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. Conclusions: 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.