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Int J Biol Sci 2024; 20(8):3046-3060. doi:10.7150/ijbs.93375 This issue Cite

Research Paper

HDAC Inhibition Sensitize Hepatocellular Carcinoma to Lenvatinib via Suppressing AKT Activation

Shuai Yan1, Lu Chen2, Hao Zhuang3, Hui Yang1, Yinmo Yang4, Ning Zhang1,5,6,✉, Rong Liu1,7,✉

1. Translational Cancer Research Center, Peking University First Hospital, Beijing 100034, China.
2. Department of Hepatobiliary Tumor, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
3. Department of Hepatic Biliary Pancreatic Surgery, Henan Cancer Hospital, Zhengzhou 450000, China.
4. Department of General Surgery, Peking University First Hospital, Beijing 100034, China.
5. International Cancer Institute, Peking University Health Science Center, Beijing 100191, China.
6. Yunnan Baiyao Group, Kunming 650504, China.
7. Southwest United Graduate School, Kunming 650092, China.

✉ Corresponding authors: Rong Liu: liurongcom; Ning Zhang: zhangningedu.cn.

Citation:
Yan S, Chen L, Zhuang H, Yang H, Yang Y, Zhang N, Liu R. HDAC Inhibition Sensitize Hepatocellular Carcinoma to Lenvatinib via Suppressing AKT Activation. Int J Biol Sci 2024; 20(8):3046-3060. doi:10.7150/ijbs.93375. https://www.ijbs.com/v20p3046.htm
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Abstract

Graphic abstract

Hepatocellular carcinoma (HCC) is a deadly malignancy with limited treatment options. As a first-line treatment for advanced HCC, Lenvatinib has been applicated in clinic since 2018. Resistance to Lenvatinib, however, has severely restricted the clinical benefits of this drug. Therefore, it is urgent to explore the potential resistance mechanisms of Lenvatinib and identify appropriate methods to reduce resistance for the treatment of HCC. We identified SAHA, a HDAC inhibitor, to have effective anti-tumor activity against Lenvatinib-resistant HCC organoids by screening a customized drug library. Mechanism analysis revealed that SAHA upregulates PTEN expression and suppresses AKT signaling, which contributes to reversing Lenvatinib resistance in liver cancer cells. Furthermore, combinational application of Lenvatinib and HDAC inhibitor or AKT inhibitor synergistically inhibits HCC cell proliferation and induces cell apoptosis. Finally, we confirmed the synergistic effects of Lenvatinib and SAHA, or AZD5363 in primary liver cancer patient derived organoids. Collectively, these findings may enable the development of Lenvatinib combination therapies for HCC.

Keywords: Hepatocellular carcinoma, Lenvatinib resistance, SAHA, AKT, combination treatment

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APA
Yan, S., Chen, L., Zhuang, H., Yang, H., Yang, Y., Zhang, N., Liu, R. (2024). HDAC Inhibition Sensitize Hepatocellular Carcinoma to Lenvatinib via Suppressing AKT Activation. International Journal of Biological Sciences, 20(8), 3046-3060. https://doi.org/10.7150/ijbs.93375.

ACS
Yan, S.; Chen, L.; Zhuang, H.; Yang, H.; Yang, Y.; Zhang, N.; Liu, R. HDAC Inhibition Sensitize Hepatocellular Carcinoma to Lenvatinib via Suppressing AKT Activation. Int. J. Biol. Sci. 2024, 20 (8), 3046-3060. DOI: 10.7150/ijbs.93375.

NLM
Yan S, Chen L, Zhuang H, Yang H, Yang Y, Zhang N, Liu R. HDAC Inhibition Sensitize Hepatocellular Carcinoma to Lenvatinib via Suppressing AKT Activation. Int J Biol Sci 2024; 20(8):3046-3060. doi:10.7150/ijbs.93375. https://www.ijbs.com/v20p3046.htm

CSE
Yan S, Chen L, Zhuang H, Yang H, Yang Y, Zhang N, Liu R. 2024. HDAC Inhibition Sensitize Hepatocellular Carcinoma to Lenvatinib via Suppressing AKT Activation. Int J Biol Sci. 20(8):3046-3060.

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