Trastuzumab is not a tyrosine kinase inhibitor

Abstract

CORRESPONDENCEWe read with great interest the Review by Ewer, M. S. & Ewer, S. M. (Cardiotoxicity of anticancer treatments. Nat. Rev. Cardiol. 12, 547-558;2015), 1 because it is highly relevant to our research. We appreciate the thorough review of the heart disorders and the associated molecular mechanisms elicited by receptor tyrosine-protein kinase erbB-2 (ERBB2)-targeted agents in this article. However, we believe that the authors' description of trastuzumab as "the first mono clonal antibody tyrosine kinase inhibitor" is conceptually incorrect and does not reflect the current state of literature in this field.Tyrosine kinase inhibitors (TKIs), such as lapatinib, inhibit the kinase activity of epidermal growth factor receptor (EGFR), and ERBB2 and ligand-induced receptor phosphorylation by reversibly binding to the ATP-binding site of the kinase. 2 Cetuximab, a therapeutic monoclonal antibody directed against the extracellular domain of EGFR, acts as a TKI to block the activation of EGFR tyrosine kinase by competing for ligand binding. 3,4 Trastuzumab is a therapeutic monoclonal antibody directed against the extracellular domain of ERBB2. 5 However, the effects of trastuzumab on ERBB2 kinase activity are different from those of TKIs and cetuximab. An anti-ERBB2 mono clonal antibody 4D5, which was later humanized to generate trastuzumab, was shown to exhibit agonistic signalling, resulting in increased ERBB2 phosphorylation that correlated with its inhibitory effect on ERBB2-overexpressing breast cancer cells. 6 Growing evidence indicates that targeting ERBB2 using trastuzumab increases ERBB2 tyrosine phosphorylation in trastuzumab-sensitive breast cancer cells. 7-9 Diemeier and colleagues reported that the inhibitory effect of trastuzumab on trastuzumab-sensitive breast

Trastuzumab-mediated cardiotoxicity: current understanding, challenges, and frontiers

“…Knowledge of the anti-tumor mechanisms of trastuzumab is constantly developing, due to better understanding of HER2-associated signaling pathways, and many aspects of mechanisms of action still need to be clarified. Accumulating data suggest that unlike tyrosine kinase inhibitors or cetuximab, a monoclonal antibody directed against epidermal growth factor receptor (EGFR), trastuzumab increases tyrosine kinase activity of HER2 and induces phosphorylation of HER2 and EGFR at tyrosine 1248 (Y1248) and tyrosine 845 (Y845), respectively, in HER2-positive breast cancer cells [6,7,8]. The enhanced HER2 phosphorylation at Y1248 increases the interaction of HER2 with non-receptor Csk-homologous kinase that negatively regulates the activity of HER2 signaling, leading to growth inhibition of breast cancer cells [6].…”