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 beta-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 inhibitors improve the anti-tumor efficacy of lenvatinib in hepatocarcinoma cells / Digiacomo, Graziana; Fumarola, Claudia; La Monica, Silvia; Bonelli, Mara; Cavazzoni, Andrea; Galetti, Maricla; Terenziani, Rita; Eltayeb, Kamal; Volta, Francesco; Zoppi, Silvia; Bertolini, Patrizia; Missale, Gabriele; Alfieri, Roberta; Petronini, Pier Giorgio. - In: FRONTIERS IN ONCOLOGY. - ISSN 2234-943X. - 12:(2022), p. 942341. [10.3389/fonc.2022.942341]

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

Digiacomo, Graziana;Fumarola, Claudia;La Monica, Silvia;Bonelli, Mara;Cavazzoni, Andrea
;
Galetti, Maricla;Terenziani, Rita;Eltayeb, Kamal;Volta, Francesco;Zoppi, Silvia;Bertolini, Patrizia;Missale, Gabriele;Alfieri, Roberta;Petronini, Pier Giorgio
2022-01-01

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 beta-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 inhibitors improve the anti-tumor efficacy of lenvatinib in hepatocarcinoma cells / Digiacomo, Graziana; Fumarola, Claudia; La Monica, Silvia; Bonelli, Mara; Cavazzoni, Andrea; Galetti, Maricla; Terenziani, Rita; Eltayeb, Kamal; Volta, Francesco; Zoppi, Silvia; Bertolini, Patrizia; Missale, Gabriele; Alfieri, Roberta; Petronini, Pier Giorgio. - In: FRONTIERS IN ONCOLOGY. - ISSN 2234-943X. - 12:(2022), p. 942341. [10.3389/fonc.2022.942341]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2928752
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