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

Primary and acquired resistance to tyrosine kinase inhibitors (TKIs) causes treatment failure in NSCLC. The molecular mechanism of drug resistance to TKIs remains largely unknown. We demonstrate that autocrine EGF and TGF- α confer primary and acquired resistance to ALK/c-Met TKIs in NSCLC. These findings suggest that close attention should be paid to the expression changes of growth factors in patients before and after treatment. AbstractDrug 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- α) 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-α in established acquired resistant H3122/TR and EBC-1/SR cells. Importantly, overexpression of EG F and TGF-α in two NSCLC cell lines produced resistance to TAE684 and SGX-523. Clinically, NSCLC patients with high expression of EGF and TGF-α developed primary resistance to crizotinib. Mechanistically, autocrine EGF and TGF-α activated EGFR signaling pathways to...
Source: Pharmacology Research and Perspectives - Category: Drugs & Pharmacology Authors: Tags: ORIGINAL ARTICLE Source Type: research