Objective: The novel compound GCJ-490A has been discovered as a pan-histone deacetylase (HDAC) inhibitor that exerts potent 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 IKKα promoter and enhanced IKKα 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.

Ting He;Yinglei Gao;Yanfen Fang;Yangming Zhang;Shuwei Zhang;Fajun Nan;Jian Ding;Yi Chen

Division of Anti-Tumor Pharmacology,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China;University of Chinese Academy of Sciences,Beijing 100049,China;State Key Laboratory of Drug Research,the National Center for Drug Screening,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China

癌症生物学与医学（英文版）

[1]Ting He;Yinglei Gao;Yanfen Fang;Yangming Zhang;Shuwei Zhang;Fajun Nan;Jian Ding;Yi Chen-.The HDAC inhibitor GCJ-490A suppresses c-Met expression through IKKα and overcomes gefitinib resistance in non-small cell lung cancer)[J].癌症生物学与医学（英文版）,2022(08):1172-1192

GCJ,490A

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