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Cabozantinib-based combination therapy for the treatment of hepatocellular carcinoma

文献类型： 外文期刊

作者： Shang, Runze 1 ; Song, Xinhua 2 ; Wang, Pan 2 ; Zhou, Yi 2 ; Lu, Xinjun 2 ; Wang, Jingxiao 7 ; Xu, Meng 8 ; Chen, Xinyan; 1 ;

作者机构： 1.Xijing Hosp, Dept Hepatobiliary Surg, Xian, Shaanxi, Peoples R China

2.Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94122 USA

3.910 Hosp, Dept Gen Surg, Quanzhou, Fujian, Peoples R China

4.Beijing Acad Agr & Forestry Sci, Beijing Vegetable Res Ctr, Collaborat Innovat Ctr Agr Prod Proc & Nutr & Hlt, Beijing, Peoples R China

5.Xi An Jiao Tong Univ, Dept Infect Dis, Affiliated Hosp 1, Xian, Shaanxi, Peoples R China

6.Sun Yat Sen Univ, Dept Hepat Surg, Affiliated Hosp 1, Guangzhou, Guangdong, Peoples R China

7.Beijing Univ Chinese Med, Sch Life Sci, Beijing, Peoples R China

8.Xi An Jiao Tong Univ, Dept Gen Surg, Hosp 2, Xian, Peoples R China

9.Hubei Univ Chinese Med, Dept Pharm, Wuhan, Hubei, Peoples R China

10.Univ Regensburg, Inst Pathol, Regensburg, Bayern, Germany

11.Legend Biotech USA Inc, R&D Ctr, Piscataway, NJ USA

12.Huazhong Univ Sci & Technol, Hepat Surg Ctr, Tongji Hosp, Tongji Med Coll, Wuhan, Hubei, Peoples R China

期刊名称：GUT （ 影响因子：23.059； 五年影响因子：22.225 ）

ISSN： 0017-5749

年卷期： 2021 年 70 卷 9 期

页码：

收录情况： SCI

摘要： Objective Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer with limited treatment options. Cabozantinib, an orally bioavailable multikinase inhibitor is now approved by Food and Drug Administration (FDA) for HCC patients. We evaluated the therapeutic efficacy of cabozantinib, either alone or in combination, in vitro and in vivo. Design Human HCC cell lines and HCC mouse models were used to assess the therapeutic efficacy and targeted molecular pathways of cabozantinib, either alone or in combination with the pan-mTOR inhibitor MLN0128 or the checkpoint inhibitor anti-PD-L1 antibody. Results Cabozantinib treatment led to stable disease in c-Met/beta-catenin and Akt/c-Met mouse HCC while possessing limited efficacy on Akt/Ras and c-Myc liver tumours. Importantly, cabozantinib effectively inhibited c-MET and ERK activity, leading to decreased PKM2 and increased p21 expression in HCC cells and in c-Met/beta-catenin and Akt/c-Met HCC. However, cabozantinib was ineffective in inhibiting the Akt/mTOR cascade. Intriguingly, a strong inhibition of angiogenesis by cabozantinib occurred regardless of the oncogenic drivers. However, cabozantinib had limited impact on other tumour microenvironment parameters, including tumour infiltrating T cells, and did not induce programmed death-ligand 1 (PD-L1) expression. Combining cabozantinib with MLN0128 led to tumour regression in c-Met/beta-catenin mice. In contrast, combined treatment with cabozantinib and the checkpoint inhibitor anti-PD-L1 antibody did not provide any additional therapeutic benefit in the four mouse HCC models tested. Conclusion c-MET/ERK/p21/PKM2 cascade and VEGFR2-induced angiogenesis are the primary targets of cabozantinib in HCC treatment. Combination therapies with cabozantinib and mTOR inhibitors may be effective against human HCC.

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