曲妥珠单抗耐药机制的最新研究进展

An updated review of the research on Her-2-targeted antibody resistance mechanisms

人类表皮生长因子受体2(human epidermal growth factor receptor 2,Her-2)在20%～25%的侵袭性乳腺癌中有过度表达,且其过度表达与乳腺癌的侵袭性和生存率相关。曲妥珠单抗(商品名:赫赛汀,herceptin)是一种已广泛应用于临床治疗的抗Her-2的单克隆抗体,其与化疗药物联用可以明显延长患者的无病生存期,但Her-2表达阳性的乳腺癌细胞易对曲妥珠单抗产生耐药性。本文系统总结了曲妥珠单抗的耐药机制及相关最新研究进展,包括PI3K/AKT信号通路过度激活、表皮生长因子受体家族(epidermal growth factor receptor family,EGFR family)及其配体的异常表达、Her-2或曲妥珠单抗封闭、胰岛素样生长因子1受体(insulin-like growth factor 1 receptor,IGF-1R)旁路活化PI3K/AKT通路、Darpp-32和t-Darpp过度表达、肿瘤细胞自体吞噬、热休克蛋白27(heat shock protein 27,HSP27)过度表达等。

Human epidermal growth factor receptor 2 （Her-2）,which is often over-expressed in 20%-25% of invasive breast cancer patients,is associated with an aggressive tumor phenotype and therefore,a reduced survival rate.As a widely clinically applied Her-2-targeted monoclonal antibody,herceptin,when combined with chemotherapy,significantly increases the survival time of patients without tumors.However,the majority of the cancers that initially respond positively to herceptin begin to counteract against the treatment within just 1 year.This study described several important and well-known mechanisms as well as the updates and advancement in this field.These mechanisms include over-activation of the PI3K/AKT pathway,abnormal expression in the EGFR family and their ligands,the masking of the Her-2 receptor,herceptin,activation of PI3K/AKT via an alternative pathway,over-expression of Darpp-32 and t-Darpp,autophagy of tumor cells and over-expression of HSP27,and more.