Trastuzumab emtansine: mechanisms of action and drug resistance.
Trastuzumab emtansine: mechanisms of action and drug resistance.
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DOI：
10.1186/bcr3621
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发表时间：
2014-03-05
期刊：
影响因子：
--
通讯作者：
Isola J
中科院分区：
文献类型：
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作者：
Barok M;Joensuu H;Isola J
曲妥珠单抗-美坦新偶联物（T-DM 1）是一种抗体-药物偶联物，当作为单一药物给药治疗晚期乳腺癌时，其有效且通常耐受良好。目前已在随机试验中证实了作为晚期乳腺癌一线、二线和二线后治疗的疗效。T-DM 1目前正在评估作为早期乳腺癌的辅助治疗。它具有几种作用机制，包括曲妥珠单抗的抗肿瘤作用和DM 1的抗肿瘤作用，DM 1是一种细胞毒性抗微管剂，在溶酶体中人表皮生长因子受体-2（HER 2）-T-DM 1复合物降解后在靶细胞内释放。T-DM 1的细胞毒性作用可能根据癌细胞中积累的DM 1的细胞内浓度而变化，高细胞内水平导致快速凋亡，稍低水平导致受损的细胞运输和有丝分裂灾难，而最低水平导致对T-DM 1的不良反应。HER 2阳性转移性乳腺癌对T-DM 1的原发性耐药似乎相对罕见，但大多数接受T-DM 1治疗的患者会出现获得性耐药。耐药机制尚未完全了解，但可能涉及限制曲妥珠单抗与癌细胞结合的机制。T-DM 1的细胞毒性作用可能因HER 2-T-DM 1复合物在癌细胞中的无效内化或增强再循环，或曲妥珠单抗的溶酶体降解或HER 2的细胞内运输受损而受损。T-DM 1的作用也可能受到将DM 1泵出癌细胞的多药耐药蛋白的影响。在这篇综述中，我们讨论了T-DM 1的作用机制和关键的临床结果，T-DM 1与其他细胞毒性药物和抗HER药物的组合，以及潜在的耐药机制和克服T-DM 1耐药的策略。
Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that is effective and generally well tolerated when administered as a single agent to treat advanced breast cancer. Efficacy has now been demonstrated in randomized trials as first line, second line, and later than the second line treatment of advanced breast cancer. T-DM1 is currently being evaluated as adjuvant treatment for early breast cancer. It has several mechanisms of action consisting of the anti-tumor effects of trastuzumab and those of DM1, a cytotoxic anti-microtubule agent released within the target cells upon degradation of the human epidermal growth factor receptor-2 (HER2)-T-DM1 complex in lysosomes. The cytotoxic effect of T-DM1 likely varies depending on the intracellular concentration of DM1 accumulated in cancer cells, high intracellular levels resulting in rapid apoptosis, somewhat lower levels in impaired cellular trafficking and mitotic catastrophe, while the lowest levels lead to poor response to T-DM1. Primary resistance of HER2-positive metastatic breast cancer to T-DM1 appears to be relatively infrequent, but most patients treated with T-DM1 develop acquired drug resistance. The mechanisms of resistance are incompletely understood, but mechanisms limiting the binding of trastuzumab to cancer cells may be involved. The cytotoxic effect of T-DM1 may be impaired by inefficient internalization or enhanced recycling of the HER2-T-DM1 complex in cancer cells, or impaired lysosomal degradation of trastuzumab or intracellular trafficking of HER2. The effect of T-DM1 may also be compromised by multidrug resistance proteins that pump DM1 out of cancer cells. In this review we discuss the mechanism of action of T-DM1 and the key clinical results obtained with it, the combinations of T-DM1 with other cytotoxic agents and anti-HER drugs, and the potential resistance mechanisms and the strategies to overcome resistance to T-DM1.