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This galley proof is being listed electronically before publishing the final manuscript (It's not final version).

Synergistic antitumor activity of sorafenib and MG149 in hepatocellular carcinoma cells
Byul Moon1,2 (Graduate student), Mijin Park1,2 (Graduate student), Seung-Hyun Cho1,3,4 (Graduate student), Kang Mo Kim5 (Professor), Haeng Ran Seo6 (Principle investigator), Jeong-Hoon Kim 1,3 (Principle investigator), Jung-Ae Kim 1,2,* (Principle investigator)
1Department of functional genomics, KRIBB school of bioscience, University of science and technology,
2Personalized genomic medicine research center and 3Disease target structure research center, Korea research institute of bioscience and biotechnology,
4R&D Center, Uppthera,
5Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine,
6Advanced Biomedical Research Laboratory, Institut Pasteur Korea
Advanced hepatocellular carcinoma (HCC) is among the most challenging cancers to overcome, and there is a need for better therapeutic strategies. Among the different cancer drugs that have been used in clinics, sorafenib is considered the standard first-line drug for advanced HCC. Here, to identify a chemical compound displaying a synergistic effect with sorafenib in HCC, we screened a focused chemical library and found that MG149, a histone acetyltransferase inhibitor targeting the MYST family, exhibited the most synergistic anticancer effect with sorafenib on HCC cells. The combination of sorafenib and MG149 exerted a synergistic anti-proliferation effect on HCC cells by inducing apoptotic cell death. We revealed that cotreatment with sorafenib and MG149 aggravated endoplasmic reticulum (ER) stress to promote the death of HCC cells rather than adaptive cell survival. In addition, combined treatment with sorafenib and MG149 significantly increased the intracellular levels of unfolded proteins and reactive oxygen species, which upregulated ER stress. Collectively, these results suggest that MG149 has the potential to improve the efficacy of sorafenib in advanced HCC via the upregulation of cytotoxic ER stress.
Abstract, Accepted Manuscript(in press) [Submitted on February 23, 2022, Accepted on June 9, 2022]
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