Shang, Runze and Song, Xinhua and Wang, Pan and Zhou, Yi and Lu, Xinjun and Wang, Jingxiao and Xu, Meng and Chen, Xinyan and Utpatel, Kirsten and Che, Li and Liang, Binyong and Cigliano, Antonio and Evert, Matthias and Calvisi, Diego F. and Chen, Xin (2021) Cabozantinib-based combination therapy for the treatment of hepatocellular carcinoma. GUT, 70 (9). pp. 1746-1757. ISSN 0017-5749, 1468-3288
Full text not available from this repository. (Request a copy)Abstract
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET; C-MET; MOUSE; DRIVEN; AKT; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 20 Sep 2022 13:08 |
| Last Modified: | 20 Sep 2022 13:08 |
| URI: | https://pred.uni-regensburg.de/id/eprint/47625 |
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