癌症相关死亡的主要原因是癌细胞向远处器官的扩散。尽管现代化疗策略在原发肿瘤阶段获得成功，但在治疗转移性疾病方面却显得无效，主要是因为耐药性的发展。适配器蛋白ezrin在多种临床前模型中被证实能够促进癌细胞转移，并与多种癌症类型，包括乳腺癌，的不良预后有关。Ezrin促进了生存信号的传递，特别是在散布的癌细胞中，以促进转移性扩展。然而，ezrin在乳腺癌化疗耐药性中的作用尚未完全了解。在本研究中，我们展示了上调或下调ezrin表达会改变体外乳腺癌细胞对多柔比星和多西他赛处理的敏感性，并与PI3K/Akt和NFκB通路激活的改变相关。此外，我们测试了小分子ezrin抑制剂NSC668394的全身治疗效果，作为单药治疗或与蒽环类或紫杉醇基化疗联合治疗的组合疗法，对体内肺转移负担的影响。我们展示了抗ezrin治疗单独降低了转移负担，并显著增强了转移灶对多柔比星或多西他赛的敏感性，无论是新辅助还是新辅助加辅助治疗模型都适用。综上所述，我们的研究结果展示了抗ezrin治疗在调节乳腺癌细胞对化疗的应答以及在减少转移负担方面与化疗联合治疗的有效性。这项研究为将抗ezrin治疗与化疗相结合，作为一种新的策略有效地靶向转移提供了临床前证据，尤其是在新辅助治疗的情况下。©2022作者；由美国癌症研究协会出版。

The main cause of cancer-associated deaths is the spread of cancer cells to distant organs. Despite its success in the primary tumor setting, modern chemotherapeutic strategies are rendered ineffective at treating metastatic disease, largely due to the development of resistance. The adaptor protein ezrin has been shown to promote cancer metastasis in multiple preclinical models and is associated with poor prognosis in several cancer types, including breast cancer. Ezrin promotes pro-survival signaling, particularly in disseminated cancer cells, to facilitate metastatic outgrowth. However, the role of ezrin in breast cancer chemoresistance is not fully known. In this study, we show that upregulating or downregulating ezrin expression modifies the sensitivity of breast cancer cells to doxorubicin and docetaxel treatment in vitro and is associated with changes in PI3K/Akt and NFκB pathway activation. In addition, we tested the effects of systemic treatment with a small-molecule ezrin inhibitor, NSC668394, on lung metastatic burden in vivo as a monotherapy, or in combination with anthracycline- or taxane-based chemotherapy treatment. We show that anti-ezrin treatment alone reduces metastatic burden and markedly sensitizes metastases to doxorubicin or docetaxel in neoadjuvant as well as neoadjuvant plus adjuvant treatment models. Taken together, our findings demonstrate the impact of anti-ezrin treatment in modulating response to chemotherapy in breast cancer cells as well as the efficacy of anti-ezrin treatment in combination with chemotherapy at reducing metastatic burden.This work provides preclinical evidence for combining anti-ezrin treatment with chemotherapy as a novel strategy for effectively targeting metastasis, particularly in a neoadjuvant treatment setting.© 2022 The Authors; Published by the American Association for Cancer Research.