Trastuzumab Is Not a Tyrosine Kinase Inhibitor Nishant Mohan and Wen Jin Wu

CORRESPONDENCE

Nature Reviews Cardiology published online 29 September 2015; doi:10.1038/nrcardio.2015.135

Trastuzumab is not a tyrosine kinase inhibitor Nishant Mohan and Wen Jin Wu

We read with great interest the Review by cancer cells is associated with its capacity to Correspondence to: W.J.W. Ewer, M. S. & Ewer, S. M. (Cardiotoxicity of induce ERBB2 phosphorylation at Tyr1248.7 [email protected] anticancer treatments. Nat. Rev. Cardiol. 12, Gijsen and co-workers also reported that Acknowledgements 1 547–558; 2015), because it is highly relevant trastuzumab induced ERBB2 tyrosine phos- We thank J. Zhou and T. S. Stantchev from the to our research. We appreciate the thorough phorylation,8 and together with another Center for Drug Evaluation and Research, U.S. Food and Drug Administration, for critical review review of the heart disorders and the asso- group observed that trastuzumab treatment of the manuscript. ciated molecular mechanisms elicited by induced paradoxical activation of mitogen- receptor tyrosine-protein kinase erbB‑2 activated protein kinase 1/3 in breast cancer Competing interests (ERBB2)-targeted agents in this article. How cells.8,9 In 2014, we demonstrated that trastu- N.M. and W.J.W are employees of the US Food and Drug Administration. This Correspondence reflects ever, we believe that the authors’ description zumab upregulated ERBB2 tyrosine kinase the views of the authors and should not be of trastuzumab as “the first monoclonal anti- activity in trastuzumab-sensitive breast construed to represent FDA’s views or policies. body tyrosine kinase inhibitor” is conceptu- cancer cells, and that this upregulated activity 9 1. Ewer, M. S. & Ewer, S. M. Cardiotoxicity of ally incorrect and does not reflect the current contributed to ERBB2 phosphorylation. anticancer treatments. Nat. Rev. Cardiol. 12, state of literature in this field. Despite different effects on ERBB2 phos- 547–558 (2015). Tyrosine kinase inhibitors (TKIs), such phorylation, both lapatinib and trastuzumab 2. Medina, P. J. & Goodin, S. Lapatinib: a dual as lapatinib, inhibit the kinase activity of have the capacity to downregulate Akt activ- inhibitor of human epidermal growth factor receptor tyrosine kinases. Clin. Ther. 8, epidermal growth factor receptor (EGFR), ity and to inhibit growth of breast cancer cells. 1426–1447 (2008). and ERBB2 and ligand-induced receptor Based on our data, we postulate that binding 3. Mendelsohn, J. & Baselga, J. Epidermal growth phosphorylation by reversibly binding to the of trastuzumab to ERBB2 could induce struc- factor receptor targeting in cancer. 2 Semin. Oncol. 33, 369–385 (2006). ATP-binding site of the kinase. Cetuximab, tural changes in the ERBB2 cytoplasmic 4. Mendelsohn, J. & Baselga, J. The EGF receptor a therapeutic monoclonal antibody directed kinase domain, leading to allosteric activa- family as targets for cancer therapy. Oncogene against the extracellular domain of EGFR, tion of ERBB2 kinase and transphosphory 19, 6550–6565 (2000). 9,10 5. Hudis, C. A. Trastuzumab—mechanism of acts as a TKI to block the activation of EGFR lation of ERBB2. Trastuzumab-induced action and use in clinical practice. N. Engl. J. tyrosine kinase by competing for ligand ERBB2 phosphorylation provides docking Med. 357, 39–51 (2007). binding.3,4 Trastuzumab is a therapeutic sites for downstream signalling molecules, 6. Scott, G. K. et al. p185HER2 signal monoclonal antibody directed against the which are different from those induced by transduction in breast cancer cells. J. Biol. 5 Chem. 266, 14300–14305 (1991). extracellular domain of ERBB2. However, a ligand (such as epidermal growth factor), 7. Diermeier, S. et al. Epidermal growth factor the effects of trastuzumab on ERBB2 kinase in that they recruit signalling molecules such receptor coexpression modulates susceptibility activity are different from those of TKIs and as Csk-homologous kinase, a non-receptor to Herceptin in HER2/neu overexpressing breast cancer cells via specific erbB-receptor cetuximab. An anti-ERBB2 monoclonal tyrosine kinase. Negative signals downstream interaction and activation. Exp. Cell. Res. 304, antibody 4D5, which was later human- of ERBB2 subsequently contribute to growth 604–619 (2005). ized to generate trastuzumab, was shown inhibition of ERBB2-positive breast cancer 8. Gijsen, M. et al. HER2 phosphorylation is to exhibit agonistic signalling, resulting in cells.9,10 Taken together, these studies provide maintained by a PKB negative feedback loop in response to anti-HER2 herceptin in breast increased ERBB2 phosphorylation that cor- evidence that trastuzumab does not function cancer. PLoS Biol. 8, e1000563 (2010). related with its inhibitory effect on ERBB2- as a TKI. 9. Dokmanovic, M. et al. Trastuzumab-induced overexpressing breast cancer cells.6 Growing recruitment of Csk-homologous kinase (CHK) to ErbB2 receptor is associated with Division of Biotechnology Research and evidence indicates that targeting ERBB2 ErbB2‑Y1248 phosphorylation and ErbB2 using trastuzumab increases ERBB2 tyrosine Review I, Office of Biotechnology Products, degradation to mediate cell growth inhibition. phosphorylation in trastuzumab-sensitive Office of Pharmaceutical Quality, Center Cancer Biol. Ther. 8, 1029–1041 (2014). 7–9 for Drug Evaluation and Research, U.S. Food 10. Dokmanovic, M. & Wu, W. J. Trastuzumab- breast cancer cells. Diemeier and col- and Drug Administration, 10903 New induced HER2 phosphorylation: exploring the leagues reported that the inhibitory effect of Hampshire Avenue, Silver Spring, MD 20993, mechanisms and implications. Receptors Clin. trastuzumab on trastuzumab-sensitive breast USA (N.M., W.J.W.). Investig. 1, e340 (2014).