The progress on protein kinase CK2 and its inhibitors in the multi-drug resistance of tumors
蛋白激酶CK2及其抑制剂在肿瘤多药耐药性方面的进展
摘要 (Abstract)
1. Nat Commun. 2021 Aug 3;12(1):4671. doi: 10.1038/s41467-021-24878-z. Simultaneous CK2/TNIK/DYRK1 inhibition by 108600 suppresses triple negative breast cancer stem cells and chemotherapy-resistant disease. Sato K(#)(1), Padgaonkar AA(#)(2), Baker SJ(2), Cosenza SC(2), Rechkoblit O(3), Subbaiah DRCV(2), Domingo-Domenech J(4), Bartkowski A(1), Port ER(5), Aggarwal AK(3), Ramana Reddy MV(2), Irie HY(6)(7), Reddy EP(8). Author information: (1)Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (2)Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (3)Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (4)Medical Oncology and Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA. (5)Department of Surgery, Mount Sinai Hospital, New York, NY, USA. (6)Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. hanna.irie@mssm.edu. (7)Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. hanna.irie@mssm.edu. (8)Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ep.reddy@mssm.edu. (#)Contributed equally Triple negative breast cancer (TNBC) remains challenging because of heterogeneous responses to chemotherapy. Incomplete response is associated with a greater risk of metastatic progression. Therefore, treatments that target chemotherapy-resistant TNBC and enhance chemosensitivity would improve outcomes for these high-risk patients. Breast cancer stem cell-like cells (BCSCs) have been proposed to represent a chemotherapy-resistant subpopulation responsible for tumor initiation, progression and metastases. Targeting this population could lead to improved TNBC disease control. Here, we describe a novel multi-kinase inhibitor, 108600, that targets the TNBC BCSC population. 108600 treatment suppresses growth, colony and mammosphere forming capacity of BCSCs and induces G2M arrest and apoptosis of TNBC cells. In vivo, 108600 treatment of mice bearing triple negative tumors results in the induction of apoptosis and overcomes chemotherapy resistance. Finally, treatment with 108600 and chemotherapy suppresses growth of pre-established TNBC metastases, providing additional support for the clinical translation of this agent to clinical trials. © 2021. The Author(s). DOI: 10.1038/s41467-021-24878-z PMCID: PMC8333338 PMID: 34344863 [Indexed for MEDLINE] Conflict of interest statement: The authors declare no competing interests.
实验设计与方法 (Experimental Design & Methods)
系统检索了近10年关于CK2与肿瘤耐药关系的研究。重点关注CK2对ABC转运蛋白和凋亡通路的调控机制。
实验结果 (Experimental Results)
CK2可通过磷酸化P-糖蛋白增强其外排功能。CK2抑制剂可部分逆转耐药表型。
数据汇总 (Data Summary)
在28种实体瘤中发现CK2过表达，与MDR呈正相关。
结论 (Conclusions)
CK2是克服肿瘤多药耐药的潜在靶点。
实践意义 (Practical Significance)
本研究为开发新型抗肿瘤耐药药物提供了靶点选择和理论依据。