Jungles Kassidy M, Bishop Caroline R, Wilson Cydnee M, Liu Meilan, Jungles Kalli R, Wilder-Romans Kari, Speers Corey W, Pierce Lori J, Rae James M
Department of Pharmacology, University of Michigan, Ann Arbor, United States.
Department of Radiation Oncology, University of Michigan, Ann Arbor, United States.
Neoplasia. 2025 Aug;66:101190. doi: 10.1016/j.neo.2025.101190. Epub 2025 Jun 9.
Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype that disproportionately impacts Black women and has limited effective therapeutic options. Consequently, there is an urgent need to develop novel approaches for the treatment of TNBC. Previously, we identified monopolar spindle kinase I (Mps1 or TTK), which is upregulated in TNBC patients after radiotherapy, as a potential therapeutic target. We found that TTK inhibition sensitizes human TNBC to radiotherapy (RT) both in vitro and in vivo; however, these studies were performed in immunodeficient models. Here, we extended those studies into syngeneic murine models of TNBC using two TTK inhibitors: empesertib and the novel TTK inhibitor CFI-402257 (also known as luvixasertib) that was recently granted FDA fast track approval in breast cancer. These studies demonstrate that TTK inhibition radiosensitizes syngeneic murine models of TNBC and increases the production of micronuclei and aneuploidy. Mechanistic studies demonstrate that TTK inhibition and RT alter the tumor immune microenvironment of TNBC by modifying the production of antitumoral type I interferon (T1IFN). In vivo, TTK inhibition sensitizes syngeneic models of TNBC to RT. Furthermore, combining TTK inhibition and RT also potentiates T1IFN signaling, suggesting that combination treatment may induce antitumoral immunity in immunocompetent models. Taken together, these studies demonstrate that TTK inhibition enhances radiosensitivity and TTK inhibition with RT modulates the immune landscape of TNBC. Collectively, this combination may represent a novel therapeutic strategy to improve outcomes for patients with TNBC by both direct tumor cytotoxicity and by promoting an immune-responsive environment.
三阴性乳腺癌（TNBC）是一种侵袭性乳腺癌亚型，对黑人女性的影响尤为严重，且有效治疗选择有限。因此，迫切需要开发治疗TNBC的新方法。此前，我们鉴定出单极纺锤体激酶I（Mps1或TTK），其在放疗后的TNBC患者中上调，是一个潜在的治疗靶点。我们发现抑制TTK可使人类TNBC在体外和体内均对放疗（RT）敏感；然而，这些研究是在免疫缺陷模型中进行的。在此，我们使用两种TTK抑制剂：恩培塞替布和新型TTK抑制剂CFI-402257（也称为鲁维沙替布，最近已获得FDA在乳腺癌方面的快速通道批准），将这些研究扩展到TNBC的同基因小鼠模型中。这些研究表明，抑制TTK可使TNBC的同基因小鼠模型对放疗敏感，并增加微核和非整倍体的产生。机制研究表明，抑制TTK和放疗通过改变抗肿瘤I型干扰素（T1IFN）的产生来改变TNBC的肿瘤免疫微环境。在体内，抑制TTK可使TNBC的同基因模型对放疗敏感。此外，联合抑制TTK和放疗还可增强T1IFN信号传导，表明联合治疗可能在免疫健全模型中诱导抗肿瘤免疫。综上所述，这些研究表明抑制TTK可增强放射敏感性，抑制TTK与放疗联合可调节TNBC的免疫格局。总体而言，这种联合可能代表一种新的治疗策略，通过直接的肿瘤细胞毒性和促进免疫反应环境来改善TNBC患者的预后。
