NF-κB activation is an early event of changes in gene regulation for acquiring drug resistance in human adenocarcinoma PC-9 cells.

Abstract

Gefitinib and erlotinib are epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Although EGFR-TKIs are effective as anti-cancer drugs, cancer cells sometimes gain tolerance to the drugs. Previous studies suggested that the fibroblast growth factor receptor (FGFR)-signaling pathway could serve as compensation for the EGFR-signaling pathway inhibited by EGFR-TKIs. Our study further suggested that FGF2, a FGFR ligand, leaked out from naïve cells killed by gefitinib could initiate the FGFR-signaling pathway in surviving cells; i.e., altruistic survival may occur in naïve cells immediately after EGFR-TKI treatment. Altruistic survival may be temporal, and cells need to change their gene regulation toward gaining resistance to EGFR-TKIs. Changes in such gene regulation after EGFR-TKI treatment are poorly understood. In this study, we examined early events of such gene regulation changes in human adenocarcinoma PC-9 cells that are capable of changing their nature from susceptibility to resistance to EFGR-TKIs. Our study indicated that activation of nuclear factor-kappa B (NF-κB) occurred in the cells immediately after EGFR-TKI treatment and also by gene silencing against oncogenic EGFR; and, MG132 treatment for inhibiting NF-κB activation affected cell viability. Taken together, our findings (including the previous study) suggest that altruistic survival and NF-κB activation might be vital for initiating the acquisition of EGFR-TKI resistance.