Inhibition of DNA-PK by gefitinib causes synergism between gefitinib and cisplatin in NSCLC

Abstract

Lung cancer has the highest incidence and mortality rates among the malignant tumor types worldwide. Platinum-based chemotherapy is the main treatment for advanced non-small-cell lung cancer (NSCLC), and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have greatly improved the survival of patients with EGFR-sensitive mutations. However, there is no standard therapy for treating patients who are EGFR-TKI resistant. Combining EGFR-TKIs and platinum-based chemotherapy is the most popular strategy in the clinical practice. However, the synergistic mechanism between EGFR-TKIs and platinum remains unknown. Therefore, the aim of the present study was to determine the synergistic mechanism of gefitinib (an EGFR-TKI) and cisplatin (a main platinum-based drug). MTT assay, apoptosis analysis, tumorsphere formation and an orthotropic xenograft mouse model were used to examine the combination effects of gefitinib and cisplatin on NSCLC. Co-immunoprecipitation and immunofluorescence were used to identify the underlying mechanism. It was found that gefitinib could selectively inhibit EGFR from entering the nucleus, decrease DNA-PK activity and enhance the cytotoxicity of cisplatin on NSCLC. Collectively, the results suggested that inhibition of DNA-dependent protein kinase by gefitinib may be due to the synergistic mechanism between gefitinib and cisplatin. Thus, the present study provides a novel insight into potential biomarkers for the selection of combination therapy of gefitinib and cisplatin.