Callegari Elisa, Guerriero Paola, Bassi Cristian, D'Abundo Lucilla, Frassoldati Antonio, Simoni Edi, Astolfi Laura, Silini Enrico Maria, Sabbioni Silvia, Negrini Massimo
Department of Translational Medicine, University of Ferrara, Via Luigi Borsari, 44121 Ferrara, Italy.
Laboratorio Per Le Tecnologie Delle Terapie Avanzate (LTTA), Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy.
Mol Ther Nucleic Acids. 2022 Jul 20;29:538-549. doi: 10.1016/j.omtn.2022.07.015. eCollection 2022 Sep 13.
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 and . 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.
帕博西尼正处于晚期肝细胞癌（HCC）的早期临床试验阶段。在此，我们研究了帕博西尼（其可阻止CDK4/6介导的RB1磷酸化，但同时激活AKT信号传导）与PI3K/AKT/mTOR抑制剂联合使用在肝癌模型中是否能提高其抗肿瘤活性。在HCC细胞系和TG221 HCC转基因小鼠模型中，测试了选择性泛AKT抑制剂MK-2206或microRNA-199a-3p与帕博西尼的联合使用情况。帕博西尼/MK-2206联合用药非常有效，但毒性太大，小鼠无法耐受。相反，miR-199a-3p模拟物/帕博西尼联合用药不仅能使肿瘤病灶完全或部分消退，而且耐受性良好。治疗3周后，与单独使用帕博西尼或miR-199a-3p模拟物相比，联合用药使肿瘤结节的数量和大小显著减少。此外，我们还报道了该联合用药对索拉非尼耐药细胞的疗效。在分子水平上，联合用药导致RB1和AKT的磷酸化同时降低。我们的研究结果为miR-199a-3p/帕博西尼联合用药作为抗HCC治疗或克服索拉非尼耐药性的新方法的疗效提供了临床前证据。
