Autocrine EGF and TGF-alpha promote primary and acquired resistance to ALK/c-Met kinase inhibitors in non-small-cell lung cancer

Drug resistance severely limits the clinical therapeutic value of molecularly targeted drugs. Growth factors gain a tremendous amount of focus due to the ability to promote drug resistance in non-small-cell lung cancer (NSCLC). However, whether tumor cells themselves can mediate drug resistance by secreting growth factors needs further clarification. Here, we first screened growth factors to identify autocrine epidermal growth factor (EGF) and transforming growth factor alpha (TGF-alpha) that caused primary resistance to the ALK inhibitor TAE684 in H3122 cells and the c-MET-specific inhibitor SGX-523 in EBC-1 cells. Next, we discovered increased autocrine production of EGF and TGF-alpha in established acquired resistant H3122/TR and EBC-1/SR cells. Importantly, overexpression of EGF and TGF-alpha in two NSCLC cell lines produced resistance to TAE684 and SGX-523. Clinically, NSCLC patients with high expression of EGF and TGF-alpha developed primary resistance to crizotinib. Mechanistically, autocrine EGF and TGF-alpha activated EGFR signaling pathways to survive targeted c-Met and ALK inhibition. Furthermore, combined treatment with gefitinib circumvented EGF- and TGF-alpha-mediated primary and acquired resistance to TAE684/SGX-523. Taken together, these results suggested increased autocrine EGF and TGF-alpha conferred primary and acquired resistance to ALK/c-Met kinase inhibitors in NSCLC.