Menapree Pimchanok, Duangthim Nattaya, Sae-Fung Apiwit, Sonkaew Sasiprapa, Jitkaew Siriporn
Graduate Program in Clinical Biochemistry and Molecular Medicine, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, 10330, Thailand.
Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, 10330, Thailand.
Sci Rep. 2025 Feb 25;15(1):6826. doi: 10.1038/s41598-025-90997-y.
Cholangiocarcinoma (CCA) is a highly aggressive bile duct cancer with a poor prognosis and high mortality rates, primarily due to the lack of early diagnosis and effective treatments. We have shown that cyclin D and CDK4/6, key regulators of cell cycle progression, are highly expressed in CCA patients. Moreover, high levels of cyclin D, CDK4, and CDK6 are associated with shorter survival in CCA patients, suggesting that cyclin D and CDK4/6 might be potential targets for CCA therapy. However, we have demonstrated that CDK4/6 inhibitor palbociclib monotherapy is less effective in CCA cells. We have identified Cellular Inhibitor of Apoptosis Proteins 1 and 2 (cIAP1/2), NF-κB target genes that their expression is associated with shorter survival in CCA patients, as potential key regulators of the CDK4/6 inhibitor response. We showed that palbociclib, a CDK4/6 inhibitor, increases phosphorylated p65 and its nuclear translocation, resulting in cIAP1/2 upregulation in CCA cells. Therefore, we hypothesized that the combination of a cIAP1/2 antagonist and a CDK4/6 inhibitor might enhance the CDK4/6 inhibitor response. Interestingly, combined treatment with the Smac mimetic LCL161, a cIAP1/2 antagonist, and palbociclib synergistically inhibits cell proliferation and induces cell death in both 2D monolayer and 3D spheroid CCA cultures. We further showed that this combination treatment has less effect on non-tumor cholangiocytes and human peripheral blood mononuclear cells (PBMCs). Our findings demonstrate for the first time that the combined treatment of Smac mimetics and CDK4/6 inhibitors is a promising novel targeted therapy for CCA patients.
胆管癌（CCA）是一种侵袭性很强的胆管癌，预后较差且死亡率高，主要原因是缺乏早期诊断和有效的治疗方法。我们已经表明，细胞周期蛋白D和CDK4/6作为细胞周期进程的关键调节因子，在CCA患者中高表达。此外，细胞周期蛋白D、CDK4和CDK6的高水平与CCA患者较短的生存期相关，这表明细胞周期蛋白D和CDK4/6可能是CCA治疗的潜在靶点。然而，我们已经证明CDK4/6抑制剂哌柏西利单药治疗在CCA细胞中效果较差。我们已经确定凋亡抑制蛋白1和2（cIAP1/2）作为CDK4/6抑制剂反应的潜在关键调节因子，它们是NF-κB靶基因，其表达与CCA患者较短的生存期相关。我们发现，CDK4/6抑制剂哌柏西利可增加磷酸化p65及其核转位，从而导致CCA细胞中cIAP1/2上调。因此，我们推测cIAP1/2拮抗剂与CDK4/6抑制剂联合使用可能会增强CDK4/6抑制剂的反应。有趣的是，cIAP1/2拮抗剂Smac模拟物LCL161与哌柏西利联合治疗可协同抑制2D单层和3D球体CCA培养物中的细胞增殖并诱导细胞死亡。我们进一步表明，这种联合治疗对非肿瘤胆管细胞和人外周血单个核细胞（PBMC）的影响较小。我们的研究结果首次证明，Smac模拟物与CDK4/6抑制剂联合治疗是一种有前景的针对CCA患者的新型靶向治疗方法。
