SHR6390 Combined with Cabozantinib Inhibits Tumor Progression in the Hepatocellular Carcinoma Mouse Model

Abstract

Background: A novel CDK4/6 inhibitor SHR6390 has shown significant anti-tumor effects. However, its role in hepatocellular carcinoma(HCC) remains unknown. Objective: To explore the inhibitory effect of combination treatment with SHR6390 and cabozantinib in HCC, and its antitumor mechanism, so as to provide more effective therapeutic strategy for HCC patients. Methods: We investigated SHR6390, monotherapy or combined with cabozantinib, by CCK8, wound healing, transwell, western blotting, immunohistochemistry and mouse model of subcutaneous tumor. Results: Our results show that SHR6390 exhibited potent anti-proliferative activity against HCC in a dose-dependent manner. SHR6390 combined with cabozantinib exhibited more potent inhibition of cell viability, migration and invasion. In terms of potential mechanisms, we found that cabozantinib could lead to phosphorylation of Rb, which was reduced in SHR6390 and combined groups. SHR6390 monotherapy inhibited the growth of subcutaneous HCC tumors, besides the combination treatment with SHR6390 and cabozantinib exerted synergistic anti-tumor activity in vivo. Conclusion: SHR6390 is effective against HCC, monotherapy or combined with cabozantinib.

Effect of Efavirenz on the Pharmacokinetics of SHR6390 in Healthy Volunteers

“…SHR6390 is an oral, efficient, and selective small molecule CDK4/6 inhibitor, that can induce the inhibition of phosphorylated Rb and cell cycle arrest at the G1 phase in both cell lines and xenografts. 7 In vivo,pharmacodynamics studies show thats SHR6390 can significantly inhibit tumor growth in mouse models of transplanted tumors 8 (including human breast cancer, ovarian cancer, and colon cancers). Pharmacokinetic studies have shown that SHR6390 has high bioavailability in rats and dogs, with a larger apparent volume of distribution, and no significant accumulation after continuous administration.…”