6/21/2023 0 Comments Protein scaffold linker payload![]() 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. 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. 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. Resistance mechanisms relating to each of these features have been demonstrated, and we outline the findings of these studies in this review. T-DM1 mediates its activity in a number of ways, encompassing HER2 signalling blockade, Fc-mediated immune response and payload-mediated microtubule poisoning. Despite its objective activity, intrinsic and acquired resistance to T-DM1 remains a major clinical challenge. 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.
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