miR-199a-3p increases the anti-tumor activity of palbociclib in liver cancer models.

Abstract

Palbociclib is in early-stage clinical testing in advanced hepatocellular carcinoma (HCC). Here, we investigated whether the anti-tumor activity of palbociclib, which prevents the CDK4/6-mediated phosphorylation of RB1 but simultaneously activates AKT signaling, could be improved by its combination with a PI3K/AKT/mTOR inhibitor in liver cancer models. The selective pan-AKT inhibitor, MK-2206, or the microRNA-199a-3p were tested in combination with palbociclib in HCC cell lines and in the TG221 HCC transgenic mouse model. The combination palbociclib/MK-2206 was highly effective, but too toxic to be tolerated by mice. Conversely, the combination miR-199a-3p mimics/palbociclib not only induced a complete or partial regression of tumor lesions, but was also well tolerated. After 3 weeks of treatment, the combination produced a significant reduction in number and size of tumor nodules in comparison with palbociclib or miR-199a-3p mimics used as single agents. Moreover, we also reported the efficacy of this combination against sorafenib-resistant cells in vitro and in vivo. At the molecular level, the combination caused the simultaneous decrease of the phosphorylation of both RB1 and of AKT. Our findings provide pre-clinical evidence for the efficacy of the combination miR-199a-3p/palbociclib as anti-HCC treatment or as a new approach to overcome sorafenib resistance.

• Authors: Elisa Callegari, Paola Guerriero, Cristian Bassi, Lucilla D'Abundo, Antonio Frassoldati, Edi Simoni, Laura Astolfi, Enrico Maria Silini, Silvia Sabbioni, Massimo Negrini
• Journal: Molecular therapy. Nucleic acids (Mol Ther Nucleic Acids) Vol. 29 Pg. 538-549 (Sep 13 2022) ISSN: 2162-2531 [Print] United States
• PMID: 36035756 (Publication Type: Journal Article)
• Copyright: © 2022 The Authors.