Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Nat Commun. 2021 Aug 3;12(1):4671. doi: 10.1038/s41467-021-24878-z.
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.
三阴性乳腺癌（TNBC）由于对化疗的反应不一致而仍然具有挑战性。不完全反应与转移性进展的风险增加相关。因此，针对化疗耐药性 TNBC 并增强化疗敏感性的治疗方法将改善这些高危患者的预后。乳腺癌干细胞样细胞（BCSCs）被认为代表了一种化疗耐药亚群，负责肿瘤的起始、进展和转移。针对该群体可能会导致 TNBC 疾病控制得到改善。在这里，我们描述了一种新型多激酶抑制剂 108600，它针对 TNBC BCSC 群体。108600 治疗抑制 BCSC 的生长、集落和类器官形成能力，并诱导 TNBC 细胞的 G2M 期阻滞和凋亡。在体内，用 108600 治疗携带三阴性肿瘤的小鼠可诱导细胞凋亡并克服化疗耐药性。最后，用 108600 和化疗联合治疗可抑制已建立的 TNBC 转移的生长，为将该药物转化为临床试验提供了更多支持。
