The effective treatment of cerebral metastases from HER2-positive breast cancer remains an unmet need. Recent studies indicate that activated astrocytes and brain endothelial cells exert chemoprotective effects on cancer cells through direct physical interaction. Here we report that the endothelin axis mediates protection of HER2-amplified brain metastatic breast cancers to the anti-HER2 antibody–drug conjugate ado-trastuzumab emtansine (T-DM1). Macitentan, a dual inhibitor of endothelin receptors A and B, improves the efficacy of T-DM1 against breast cancers grown in the brain. We show that direct contact of brain stroma with cancer cells is required for protection to T-DM1. Our data suggest that targeting the endothelin axis may be beneficial when anti-signaling agent and cytotoxic agent are combined. These findings may contribute to the development of therapeutic approaches with enhanced efficacy in the brain microenvironment.

有效治疗HER2阳性乳腺癌的脑转移仍未得到满足。最近的研究表明，活化的星形胶质细胞和脑内皮细胞通过直接的物理相互作用对癌细胞产生化学保护作用。在这里我们报告内皮素轴介导对HER2的保护抗HER2抗体-药物偶联物阿杜曲妥珠单抗（A-曲妥珠单抗）（T-DM1）扩增的脑转移性乳腺癌。Macitentan是内皮素受体A和B的双重抑制剂，可提高T-DM1对抗脑中生长的乳腺癌的功效。我们表明，脑基质与癌细胞的直接接触是保护T-DM1所必需的。我们的数据表明，结合使用抗信号传导剂和细胞毒性剂时，靶向内皮素轴可能是有益的。这些发现可能有助于开发在脑微环境中具有增强功效的治疗方法。