Palbociclib is in early-stage clinical testing in advanced hepato-cellular 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.

miR-199a-3p increases the anti-tumor activity of palbociclib in liver cancer models / Callegari, Elisa; Guerriero, Paola; Bassi, Cristian; D'Abundo, Lucilla; Frassoldati, Antonio; Simoni, Edi; Astolfi, Laura; Silini, Enrico Maria; Sabbioni, Silvia; Negrini, Massimo. - In: MOLECULAR THERAPY NUCLEIC ACIDS. - ISSN 2162-2531. - 29:(2022), pp. 538-549. [10.1016/j.omtn.2022.07.015]

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

Silini, Enrico Maria;
2022-01-01

Abstract

Palbociclib is in early-stage clinical testing in advanced hepato-cellular 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.
2022
miR-199a-3p increases the anti-tumor activity of palbociclib in liver cancer models / Callegari, Elisa; Guerriero, Paola; Bassi, Cristian; D'Abundo, Lucilla; Frassoldati, Antonio; Simoni, Edi; Astolfi, Laura; Silini, Enrico Maria; Sabbioni, Silvia; Negrini, Massimo. - In: MOLECULAR THERAPY NUCLEIC ACIDS. - ISSN 2162-2531. - 29:(2022), pp. 538-549. [10.1016/j.omtn.2022.07.015]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2953064
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