Gefitinib-mediated ROS instigates mitochondrial dysfunction and drug resistance in lung cancer cells [Molecular Bases of Disease]

February 13th, 2015 by Okon, I. S., Coughlan, K. A., Zhang, M., Wang, Q., Zou, M.-H.

Therapeutic benefits offered by tyrosine kinase inhibitors (TKIs), such as gefitinib (Iressa) and erlotinib (Tarceva) are limited due to the development of resistance which contributes to treatment failure and cancer-related mortality. The aim of this study was to elucidate mechanistic insight on cellular perturbations that accompany acquired gefitinib resistance in lung cancer cells. Several lung adenocarcinoma (LAD) cell lines were screened to characterize EGFR expression and mutation profile. In order to circumvent intrinsic variations between cell lines with respect to response to drug treatments, we generated gefitinib-resistant H1650 clone by long-term, chronic culture under gefitinib selection of parental cell line. Isogenic cells were analyzed by microarray, western blot, flow cytometry, confocal and transmission electron microscope. We observed that while chronic gefitinib treatment provided effective action against its primary target (aberrant EGFR activity), secondary effects resulted in increased cellular reactive oxygen species (ROS). Gefitinib-mediated ROS correlated with EMT, as well as striking perturbation of mitochondrial morphology and function. However, gefitinib treatment in the presence of ROS scavenger provided a partial rescue of mitochondrial aberrations. Furthermore, withdrawal of gefitinib from previously resistant clones correlated with normalized expression of EMT genes. These findings demonstrate that chronic gefitinib treatment promotes ROS and mitochondrial dysfunction in lung cancer cells. Antioxidants may alleviate ROS-mediated resistance.