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Mechanisms of resistance to trastuzumab emtansine (T-DM1) in HER2-positive breast cancer.
British Journal of Cancer ( IF 8.8 ) Pub Date : 2019-12-16 , DOI: 10.1038/s41416-019-0635-y
Francis W Hunter 1, 2 , Hilary R Barker 1 , Barbara Lipert 1 , Françoise Rothé 3 , Géraldine Gebhart 3 , Martine J Piccart-Gebhart 3 , Christos Sotiriou 3 , Stephen M F Jamieson 1, 2, 4
Affiliation  

The HER2-targeted antibody-drug conjugate trastuzumab emtansine (T-DM1) is approved for the treatment of metastatic, HER2-positive breast cancer after prior trastuzumab and taxane therapy, and has also demonstrated efficacy in the adjuvant setting in incomplete responders to neoadjuvant therapy. Despite its objective activity, intrinsic and acquired resistance to T-DM1 remains a major clinical challenge. T-DM1 mediates its activity in a number of ways, encompassing HER2 signalling blockade, Fc-mediated immune response and payload-mediated microtubule poisoning. Resistance mechanisms relating to each of these features have been demonstrated, and we outline the findings of these studies in this review. In our overview of the substantial literature on T-DM1 activity and resistance, we conclude that the T-DM1 resistance mechanisms most strongly supported by the experimental data relate to dysfunctional intracellular metabolism of the construct and subversion of DM1-mediated cell killing. Loss of dependence on signalling initiated by HER2-HER2 homodimers is not substantiated as a resistance mechanism by clinical or experimental studies, and the impact of EGFR expression and tumour immunological status requires further investigation. These findings are instructive with respect to strategies that might overcome T-DM1 resistance, including the use of second-generation anti-HER2 antibody-drug conjugates that deploy alternative linker-payload chemistries.

中文翻译:

HER2阳性乳腺癌患者对曲妥珠单抗氨丹宁(T-DM1)的耐药机制。

靶向HER2的抗体-药物结合物曲妥珠单抗emtansine(T-DM1)在先前的曲妥珠单抗和紫杉烷治疗后被批准用于治疗转移性HER2阳性乳腺癌,并且在新辅助治疗反应不完全的佐剂中也显示出疗效。尽管具有客观活性,但对T-DM1的固有和获得性耐药仍然是主要的临床挑战。T-DM1以多种方式介导其活性,包括HER2信号传导阻滞,Fc介导的免疫反应和有效载荷介导的微管中毒。已经证明了与这些特征相关的抗药性机制,我们在本综述中概述了这些研究的发现。在我们对有关T-DM1活性和抗性的大量文献的概述中,我们得出的结论是,实验数据最强烈支持的T-DM1耐药机制与构建体的功能紊乱的细胞内新陈代谢以及DM1介导的细胞杀灭的颠覆有关。临床或实验研究未将对HER2-HER2同型二聚体引发的信号传导依赖性的丧失确定为耐药机制,并且EGFR表达和肿瘤免疫状态的影响尚需进一步研究。这些发现对于可能克服T-DM1耐药性的策略具有指导意义,包括使用第二代抗HER2抗体-药物偶联物,这些偶联物可采用替代的连接子-有效负载化学物质。临床或实验研究未将对HER2-HER2同型二聚体引发的信号传导依赖性的丧失确定为耐药机制,并且EGFR表达和肿瘤免疫状态的影响尚需进一步研究。这些发现对于可能克服T-DM1耐药性的策略具有指导意义,包括使用第二代抗HER2抗体-药物偶联物,这些偶联物可采用替代的连接子-有效负载化学物质。临床或实验研究未证实对HER2-HER2同型二聚体引发的信号传导的依赖性丧失是抗药性机制,EGFR表达和肿瘤免疫状态的影响尚需进一步研究。这些发现对于可能克服T-DM1耐药性的策略具有指导意义,包括使用第二代抗HER2抗体-药物偶联物,这些偶联物可采用替代的连接子-有效负载化学物质。
更新日期:2019-12-17
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