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

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

  • Mol Ther Nucleic Acids. 2022 Jul 20:29:538-549. doi: 10.1016/j.omtn.2022.07.015.
Elisa Callegari 1,  Paola Guerriero 1 2,  Cristian Bassi 1 2,  Lucilla D'Abundo 1,  Antonio Frassoldati 1,  Edi Simoni 3,  Laura Astolfi 3,  Enrico Maria Silini 4,  Silvia Sabbioni 2 5,  Massimo Negrini 1 2
Affiliations

Affiliations

  • 1 Department of Translational Medicine, University of Ferrara, Via Luigi Borsari, 44121 Ferrara, Italy.
  • 2 Laboratorio Per Le Tecnologie Delle Terapie Avanzate (LTTA), Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy.
  • 3 Bioacoustics Research Laboratory, Department of Neurosciences, University of Padua, 35129 Padua, Italy.
  • 4 Section of Anatomy and Pathology, University Hospital of Parma, 43121 Parma, Italy.
  • 5 Department of Life Sciences and Biotechnology, University of Ferrara, Via Luigi Borsari, 44121 Ferrara, Italy.
PMID: 36035756 DOI: 10.1016/j.omtn.2022.07.015
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.

Keywords

HCC; MK-2206; Oligonucleotides: Therapies and Applications; anti-tumor therapy; mir-199a-3p; palbociclib; sorafenib resistance.

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