CDK4/6 inhibitors improve the anti-tumor efficacy of lenvatinib in hepatocarcinoma cells

Abstract

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer with a poor prognosis and limited treatment options. Considering that alterations of the CDK4/6-cyclin D-Rb pathway occur frequently in HCC, we tested the efficacy of two CDK4/6 inhibitors, abemaciclib and ribociclib, in combination with lenvatinib, a multi-kinase inhibitor approved as first-line therapy for advanced HCC, in a panel of HCC Rb-expressing cell lines. The simultaneous drug combinations showed a superior anti-proliferative activity as compared with single agents or sequential schedules of treatment, either in short or in long-term experiments. In addition, the simultaneous combination of abemaciclib with lenvatinib reduced 3D cell growth, and impaired colony formation and cell migration. Mechanistically, these growth-inhibitory effects were associated with a stronger down-regulation of c-myc protein expression. Depending on the HCC cell model, reduced activation of MAPK, mTORC1/p70S6K or src/FAK signaling was also observed. Abemaciclib combined with lenvatinib arrested the cells in the G1 cell cycle phase, induced p21 accumulation, and promoted a stronger increase of cellular senescence, associated with elevation of β-galactosidase activity and accumulation of ROS, as compared with single treatments. After drug withdrawal, the capacity of forming colonies was significantly impaired, suggesting that the anti-tumor efficacy of abemaciclib and lenvatinib combination was persistent.Our pre-clinical results demonstrate the effectiveness of the simultaneous combination of CDK4/6 inhibitors with lenvatinib in HCC cell models, suggesting that this combination may be worthy of further investigation as a therapeutic approach for the treatment of advanced HCC.

CDK4/6 Inhibition Enhances the Efficacy of Standard Chemotherapy Treatment in Malignant Pleural Mesothelioma Cells

“…As shown in Figure 2 , the treatment with abemaciclib, alone or combined with chemotherapy, reduced CDK6 phosphorylation at Y24 in all cell lines analyzed. Considering that Y24-phosphorylation is inhibitory, this is a peculiar result, emerged also in other cell models [ 22 , 23 ]. Nevertheless, abemaciclib treatment resulted in the inhibition of CDK4/6-cyclin D complex activity.…”

Exploring cyclin-dependent kinase inhibitors: a comprehensive study in search of CDK-6 inhibitors using a pharmacophore modelling and dynamics approach

“…Moreover, this therapeutic strategy shows potential for extending its benets to other solid tumours, such as pancreatic, and biliary cancers, cholangiocarcinoma, and pancreatic ductal adenocarcinoma, offering promising results in combatting various types of cancer. 11,12 Several particular inhibitors of CDK4 and CDK6 have gained approval from the USFDA for the progressive ER+, HER2-negative breast cancer treatment. Drugs like Palbociclib, Ribociclib, Flavopiridol, and Abemaciclib are a few of the known CDK inhibitors.…”