曲妥珠单抗（trastuzumab;商品名为Herceptin，赫赛汀）是靶向人表皮生长因子受体2（human epidermal growth factor receptor 2，HER2）的人源化单克隆抗体，与化疗药物联用可显著提高患者的无进展生存期。然而，曲妥珠单抗的原发性和获得性耐药严重制约了其临床疗效及应用。PI3K/AKT/mTOR信号通路的异常活化、HER家族成员间的相互作用、药物压力下代偿性生存信号的激活、肿瘤干细胞表型形成等均可能成为曲妥珠单抗耐药的重要机制。随着曲妥珠单抗耐药机制研究的不断深入，克服耐药的治疗手段也越来越丰富。有研究表明，曲妥珠单抗与其他靶向HER2胞外域的单克隆抗体或靶向其他HER家族成员的抗体类药物联用可增强曲妥珠单抗的疗效。应用PI3K/AKT/mTOR信号通路的小分子抑制剂或耐药相关促生存信号通路的特异性抑制剂可有效逆转耐药发生，延长患者的疾病无进展生存期。深入研究曲妥珠单抗耐药的机制，不断探索逆转耐药的治疗策略，可为乳腺癌个性化治疗方案的建立提供依据。本文将对曲妥珠单抗耐药机制及克服耐药的研究进展做一介绍。

Trastuzumab is a humanized monoclonal antibody targeting human epidermal growth factor receptor 2(HER2), which combined with chemotherapy drugs could significantly improve progression-free survival of patients. However, primary and acquired resistances of trastuzumab severely limit its curative effect and clinical application. Aberrant activation of PI3K/AKT/mTOR signaling pathway, interaction of HER family members, activation of compensatory survival signals under drug pressure and formation of phenotypes of cancer stem cells could be important mechanisms of the trastuzumab resistance. With deepening of research on mechanisms of trastuzumab resistance, treatments for overcoming trastuzumab resistance is also increasing. Some studies have shown that combination of trastuzumab with another monoclonal antibodies targeting HER2 extracellular domain or other HER family members could increase curative effect of trastuzumab. Application of small-molecule inhibitor of PI3K/AKT/mTOR signaling pathway or specific inhibitors of pro-survival signaling pathway that related to trastuzumab resisitance could effectively reverse the resistance and prolong progression-free survival of patients. In-depth researches on mechanisms of trastuzumab resistance and constant exploration on treatment strategies to reverse the resistance could provide the basis for establishment of individualized treatment plan of breast carcinoma.

国家重大新药创制资助项目（No. 2013ZX09102056）；国家高技术研究发展计划（863计划）资助项目（No. 2014AA020604）；国家自然科学基金资助项目（No. 31370825，81272232，81402562，81572845，81401311，31500702）；国家博士后基金资助项目（No. 2015T81095）；北京市自然科学基金资助项目（No. 7122124，7132163）