P70S6K Promotes Acquired Resistance Of Erlotinib Through Induction Of Epithelial-Mesenchymal Transition In Non-Small Cell Lung Carcinoma

Lung cancer is the leading cause of cancer related deaths. EGFR tyrosine kinase inhibitors, such as erlotinib, are a breakthrough for non-small cell lung carcinoma therapy. However, the acquired resistance of these inhibitors is a serious problem in clinic. Therefore, identifying and clarifying the mechanism of drug resistance, and developing new rationales to overcome resistance or enhance the effects of these inhibitors are urgently needed. In this study, we found that HCC827 cells with acquired resistance underwent epithelial-mesenchymal transition in parallel with upregulation of p70S6K as compared with its parental erlotinib sensitive cells. Moreover, downregulation of p70S6K expression both transiently using siRNA and stably using lentivirus-mediated shRNA reversed EMT and partially overcomes erlotinib resistance in erlotinib resistant cells. Meanwhile, overexpression of p70S6K promoted EMT and induced erlotinib resistance in erlotinib sensitive cells. Notably, the upregulation of p70S6K in erlotinib resistant cells is correlated with upregulation of mTORC1 and reduced ubiquitin-mediated protein degradation regulated by GSK3β. Furthermore, downregulation of p70S6K suppressed the growth of erlotinib resistant xenografts in a nude mice model. Our findings suggest that p70S6K-induced EMT plays an important role in the acquired resistance of erlotinib and provide a novel therapeutic rationale of targeting p70S6K for NSCLC therapy.