三阴性乳腺癌干细胞与化疗耐药克星
三阴性乳腺癌的雌激素受体ER、孕激素受体PR、人类表皮生长因子受体HER2均为阴性，故对常用的内分泌治疗和HER2靶向治疗无效，而且容易发生化疗耐药，复发或转移风险较高。因此，针对三阴性乳腺癌化疗耐药并增强化疗敏感性的治疗方法将改善这些高风险患者的结局。既往研究发现，干细胞样乳腺癌细胞可能是造成肿瘤形成、进展和转移的化疗耐药亚群，靶向抑制该亚群可能改善三阴性乳腺癌的病变控制。
2021年8月3日，英国《自然》旗下《自然通讯》在线发表纽约西奈山医院、伊坎医学院、托马斯杰斐逊大学的研究报告，发现一种新型多激酶抑制剂108600可靶向抑制三阴性乳腺癌干细胞亚群和化疗耐药病变。
根据体外细胞实验，108600通过同时抑制蛋白质激酶CK2、TNIK、DYRK1可抑制三阴性乳腺癌干细胞的生长、克隆和成球能力，并诱导三阴性乳腺癌细胞有丝分裂周期停滞于DNA合成后期→有丝分裂期，造成细胞凋亡。
根据小鼠体内实验，108600可诱导三阴性乳腺癌细胞凋亡并克服化疗耐药。
因此，该研究结果表明，108600联合化疗可抑制三阴性乳腺癌转移生长，为该药物向人体临床研究转化奠定了基础。
相关链接
Nat Commun. 2021 Aug 3;12:4671.
Simultaneous CK2/TNIK/DYRK1 inhibition by 108600 suppresses triple negative breast cancer stem cells and chemotherapy-resistant disease.
Katsutoshi Sato, Amol A. Padgaonkar, Stacey J. Baker, Stephen C. Cosenza, Olga Rechkoblit, D. R. C. Venkata Subbaiah, Josep Domingo-Domenech, Alison Bartkowski, Elisa R. Port, Aneel K. Aggarwal, M. V. Ramana Reddy, Hanna Y. Irie, E. Premkumar Reddy.
Icahn School of Medicine at Mount Sinai, New York, NY, USA; Thomas Jefferson University, Philadelphia, PA, USA; Mount Sinai Hospital, New York, NY, USA.
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.
DOI: 10.1038/s41467-021-24878-z
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