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Oncol Rep. 2019 Jan;41(1):525-533. doi: 10.3892/or.2018.6814. Epub 2018 Oct 22.

Vorinostat enhances gefitinib‑induced cell death through reactive oxygen species‑dependent cleavage of HSP90 and its clients in non‑small cell lung cancer with the EGFR mutation.

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Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.


Although different mechanisms of acquired resistance to epidermal growth factor receptor (EGFR)‑tyrosine kinase inhibitors (TKIs) have been reported in non‑small cell lung cancers (NSCLCs), the optimal treatment for patients with acquired resistance has not been clearly defined. The purpose of this study was to investigate the antitumor effects of gefitinib in combination with vorinostat, a potent histone deacetylase inhibitor (HDACI), and their associated molecular mechanisms in relation to activating apoptosis in NSCLC. The treatment using a combination of vorinostat and gefitinib was more potent in promoting cell death by activating apoptosis than gefitinib alone in parental PC9 cells that harbor an EGFR‑activating mutation (EGFR exon 19 deletion) and gefitinib‑resistant PC9 cells (PC9GR) with an EGFR T790M mutation. This combination induced heat shock protein 90 (HSP90) cleavage and reduced the level of HSP90 client proteins, including EGFR, MET and AKT, in PC9 and PC9GR cells. The addition of 4‑(2‑aminoethyl) benzenesulfonyl fluoride hydrochloride, a scavenger of reactive oxygen species (ROS), inhibited the degradation of HSP90 client proteins and HSP90 cleavage that was induced by co‑treatment as well as the cleavage of caspase‑3, caspase‑8, and caspase‑9 and cell death. We also observed that cleavage of HSP90 and its clients were blocked when caspases were inhibited. These results revealed that co‑treatment with vorinostat and gefitinib induced ROS‑dependent caspase activation, leading to the downregulation of HSP90 clients through HSP90 cleavage. Collectively, our findings provide a new basis for strategies that combine vorinostat with an EGFR‑TKI to reverse EGFR‑TKI resistance in NSCLC.

[Indexed for MEDLINE]

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