The HDAC inhibitor GCJ-490A suppresses c-Met expression through IKK? and overcomes gefitinib resistance in non-small cell lung cancer

inhibitory activity against HDAC1, HDAC3, and HDAC6. Because of the important roles of HDACs in lung cancer development and the high distribution of GCJ-490A in lung tissue, we explored the anti-tumor potency of GCJ-490A against non-small cell lung cancer (NSCLC) in vitro and in vivo in this study. Methods: The in vitro effects of GCJ-490A alone or combined with the EGFR inhibitor gefitinib against NSCLC were measured with proliferation, apoptosis, and colony formation assays. NSCLC xenograft models were used to investigate the efficacy of GCJ-490A combined with gefitinib for the treatment of NSCLC in vivo. Western blot assays, luciferase reporter assays, chromatin immunoprecipitation assays, quantitative real time-PCR, immunohistochemistry, and transcription factor activity assays were used to elucidate possible mechanisms. Results: GCJ-490A effectively inhibited NSCLC cell proliferation and induced apoptosis in vitro and in vivo. Interestingly, inhibition of HDAC1 and HDAC6 by GCJ-490A increased histone acetylation at the IKK?? promoter and enhanced IKK?? transcription, thus decreasing c-Met. Moreover, this c-Met downregulation was found to be essential for the synergistic anti-tumor activity of GCJ-490A and gefitinib. Conclusions: These findings highlight the promising potential of HDAC inhibitors in NSCLC treatment and provide a rational basis for the application of HDAC inhibitors in combination with EGFR inhibitors in clinical trials.

Automated summary

This study found that GCJ-490A effectively inhibited the proliferation of NSCLC cells and induced apoptosis both in vitro and in vivo. Furthermore, GCJ-490A increased histone acetylation at the IKK?? promoter by inhibiting HDAC1 and HDAC6, resulting in the downregulation of c-Met. This downregulation was essential for the synergistic anti-tumor activity of GCJ-490A and gefitinib. These findings provide a potential strategy for NSCLC treatment by using HDAC inhibitors in combination with EGFR inhibitors.