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Synergistic antitumor effect of histone deacetylase class IIa inhibitor with lenvatinib in hepatocellular carcinoma

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Abstract

Background

Histone deacetylase (HDAC) class I and IIa are highly expressed in hepatocellular carcinoma (HCC) and associated with decreased survival. However, clinically used pan and class I inhibitors have serious adverse events. In this study, we assessed the antitumor effects and tolerability of class IIa HDAC inhibitor (HDACI) with lenvatinib, which is a standard therapy for HCC.

Methods and result

Combination therapy with class IIa HDACI and lenvatinib exerted synergistic antitumor effect in human HCC cell lines. In mouse models, this therapy showed significant antitumor effects, and few adverse events occurred. In immunoblotting, the expression of fibroblast growth factor receptor 4 (FGFR4) and fibroblast growth factor 19 (FGF19) was high in cell lines that showed a high antitumor effect. In addition, class IIa HDACI administration decreased the expression of FGFR4. In the small interfering RNA (siRNA) analysis, knockdown of HDAC9, which is an isoform of HDAC class IIa, reduced the expression of FGFR4 and induced apoptosis. Immunohistochemistry of human clinical specimens showed a positivity rate of 32% for FGFR4 and 84% for HDAC9 in HCC, and all FGFR4-positive patients were HDAC9 positive.

Conclusion

Class IIa HDACI and lenvatinib combination therapy induces apoptosis by downregulating FGFR4 and blocking the FGFR signaling in FGFR4-positive HCC cell lines and has demonstrated synergistic antitumor effects and safety. This combination therapy overcomes the problems of conventional therapies and will be beneficial for FGFR4-positive HCC patients.

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Data availability

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.

Abbreviations

HCC:

Hepatocellular carcinoma

ORR:

Objective response rate

MKI:

Multi-kinase inhibitor

HDAC:

Histone deacetylase

HDACI:

HDAC inhibitor

IVIS:

In vivo bioluminescence imaging system

siRNA:

Small interfering RNA

FGFR:

Fibroblast growth factor receptor

FGF:

Fibroblast growth factor

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Acknowledgements

The authors would like to thank for Michitoshi Kimura and Mami Yamaguchi (Biomedical Research Center Division of Morphological Research, Sapporo Medical University School of Medicine, Sapporo, Japan) their technical assistance in immunohistochemical determination.

Funding

This work was supported by JSPS KAKENHI Grant Number JP18K07914.

Author information

Author notes

  1. Ryo Ito and Koji Miyanishi have contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Oncology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan

    Ryo Ito, Koji Miyanishi, Tomohiro Kubo, Kota Hamaguchi, Takahiro Osuga, Shingo Tanaka, Hiroyuki Ohnuma, Kazuyuki Murase, Kohichi Takada & Junji Kato

  2. Department of Infection Control and Laboratory Medicine, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, 060-8543, Japan

    Shingo Tanaka

  3. Department of Surgery, Surgical Oncology and Science, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, 060-8543, Japan

    Minoru Nagayama, Yasutoshi Kimura, Toru Mizuguchi & Ichiro Takemasa

  4. Postgraduate School of Health Science and Medicine, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, 060-8543, Japan

    Toru Mizuguchi

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  1. Ryo Ito
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Contributions

KM, TK, KH, and TO: conceptualization, design, data curation, formal analysis, investigation, methodology, project administration, resources, visualization, writing—original draft. ST, HO, KM, KT, MN, YK, TM, IT, and JK: investigation, resources, writing—review and editing. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Koji Miyanishi.

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Conflict of interest

The authors have not disclosed any competing interests.

Ethical approval

All mouse experiments were approved by the Animal Care and Use Committee of Sapporo Medical University School of Medicine (number of ethics approvals 20–100) and followed national guidelines.

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Ito, R., Miyanishi, K., Kubo, T. et al. Synergistic antitumor effect of histone deacetylase class IIa inhibitor with lenvatinib in hepatocellular carcinoma. Hepatol Int 17, 735–744 (2023). https://doi.org/10.1007/s12072-023-10484-2

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