Triple-negative breast cancers (TNBCs) are clinically aggressive subtypes of breast cancer. TNBC is difficult to treat with targeted agents due to the lack of commonly targeted therapies within this subtype. Androgen receptor (AR) has been detected in 12–55% of TNBCs. AR stimulates breast tumor growth in the absence of estrogen receptor (ER), and it has become an emerging molecular target in TNBC treatment. Ceritinib is a small molecule inhibitor of tyrosine kinase and it is used in the therapy of non-small lung cancer patients. Enzalutamide is a small molecule compound targeting the androgen receptor and it is used to treat prostate cancer. Combination therapy of these drugs were investigated using AR positive breast cancer mouse xenograft models. Also, combination treatment of ceritinib and paclitaxel investigated using AR− and AR low mouse xenograft and patient derived xenograft models. We screened 133 FDA approved drugs that have a therapeutic effect of AR+ TNBC cells. From the screen, we identified two drugs, ceritinib and crizotinib. Since ceritinib has a well- defined role in androgen independent AR signaling pathways, we further investigated the effect of ceritinib. Ceritinib treatment inhibited RTK/ACK/AR pathway and other downstream pathways in AR+ TNBC cells. The combination of ceritinib and enzalutamide showed a robust inhibitory effect on cell growth of AR+ TNBC cells in vitro and in vivo. Interestingly Ceritinib inhibits FAK-YB-1 signaling pathway that leads to paclitaxel resistance in all types of TNBC cells. The combination of paclitaxel and ceritinib showed drastic inhibition of tumor growth compared to a single drug alone. To improve the response of AR antagonist in AR positive TNBC, we designed a novel combinational strategy comprised of enzalutamide and ceritinib to treat AR+ TNBC tumors through the dual blockade of androgen-dependent and androgen-independent AR signaling pathways. Furthermore, we introduced a novel therapeutic combination of ceritinib and paclitaxel for AR negative or AR-low TNBCs and this combination inhibited tumor growth to a great extent. All agents used in our study are FDA-approved, and thus the proposed combination therapy will likely be useful in the clinic.

中文翻译：

---

色瑞替尼（Ceritinib）是一种新型三阴性乳腺癌治疗药物


三阴性乳腺癌（TNBC）是临床上具有侵袭性的乳腺癌亚型。 TNBC 很难用靶向药物治疗，因为该亚型缺乏通用的靶向治疗。 12-55% 的 TNBC 中检测到了雄激素受体 (AR)。 AR 在缺乏雌激素受体 (ER) 的情况下刺激乳腺肿瘤生长，它已成为 TNBC 治疗中的新兴分子靶点。色瑞替尼是一种小分子酪氨酸激酶抑制剂，用于治疗非小细胞肺癌患者。恩杂鲁胺是一种针对雄激素受体的小分子化合物，用于治疗前列腺癌。使用 AR 阳性乳腺癌小鼠异种移植模型研究了这些药物的联合治疗。此外，还使用 ​​AR− 和 AR 低小鼠异种移植模型以及患者来源的异种移植模型研究了色瑞替尼和紫杉醇的联合治疗。我们筛选了 133 种 FDA 批准的对 AR+ TNBC 细胞有治疗作用的药物。从筛选中，我们确定了两种药物：色瑞替尼和克唑替尼。由于色瑞替尼在雄激素非依赖性 AR 信号通路中具有明确的作用，因此我们进一步研究了色瑞替尼的作用。色瑞替尼治疗抑制 AR+ TNBC 细胞中的 RTK/ACK/AR 通路和其他下游通路。色瑞替尼和恩杂鲁胺的组合在体外和体内对 AR+ TNBC 细胞的生长具有强大的抑制作用。有趣的是，Ceritinib 抑制 FAK-YB-1 信号通路，从而导致所有类型的 TNBC 细胞产生紫杉醇耐药性。与单独使用单一药物相比，紫杉醇和色瑞替尼的组合显示出对肿瘤生长的显着抑制。 为了改善 AR 阳性 TNBC 中 AR 拮抗剂的反应，我们设计了一种由恩杂鲁胺和色瑞替尼组成的新型组合策略，通过双重阻断雄激素依赖性和雄激素非依赖性 AR 信号通路来治疗 AR+ TNBC 肿瘤。此外，我们还推出了一种新的色瑞替尼和紫杉醇组合治疗 AR 阴性或 AR 低 TNBC，该组合在很大程度上抑制了肿瘤生长。我们研究中使用的所有药物均已获得 FDA 批准，因此拟议的联合疗法可能在临床中有用。