Breast Cancer Research and Treatment

, Volume 134, Issue 2, pp 595–602 | Cite as

Mechanisms of cardiotoxicity associated with ErbB2 inhibitors

  • Carmine Fedele
  • Gennaro Riccio
  • Angela Eliana Malara
  • Giuseppe D’Alessio
  • Claudia De Lorenzo
Preclinical Study


The ErbB2 receptor is a proto-oncogene associated with a poor prognosis in breast cancer. Herceptin, the only humanized anti-ErbB2 antibody currently in clinical use, has proven to be an essential tool in the immunotherapy of breast carcinoma, but induces cardiotoxicity. ErbB2 is involved in the growth and survival pathway of adult cardiomyocytes; however, its levels in the adult heart are much lower than those found in breast cancer cells, the intended targets of anti-ErbB2 antibodies. Furthermore, clinical trials have shown relatively low cardiotoxicity for Lapatinib, a dual kinase inhibitor of EGFR and ErbB2, and Pertuzumab, a new anti-ErbB2 monoclonal antibody currently in clinical trials, which recognizes an epitope distant from that of Herceptin. A novel human antitumor compact anti-ErbB2 antibody, Erb-hcAb, selectively cytotoxic for ErbB2-positive cancer cells in vitro and vivo, recognizes an epitope different from that of Herceptin, and does not show cardiotoxic effects both in vitro on rat and human cardiomyocytes and in vivo on a mouse model. We investigated the molecular basis of the different cardiotoxic effects among the ErbB2 inhibitors by testing their effects on the formation of the Neuregulin 1β (NRG-1)/ErbB2/ErbB4 complex and on the activation of its downstream signaling. We report herein that Erb-hcAb at difference with Herceptin, 2C4 (Pertuzumab) and Lapatinib, does not affect the ErbB2–ErbB4 signaling pathway activated by NRG-1 in cardiac cells. These findings may have important implications for the mechanism and treatment of anti-ErbB2-induced cardiotoxicity.


ErbB2/Her2 Cancer therapy Cardiotoxicity Herceptin/trastuzumab Lapatinib 



Human fetal cardiomyocytes


Single chain fragment variable


Erbicin-human-compact antibody


Neuregulin 1β



The authors wish to thank Dr. Philip Cunnah (Biotecnol, S.A., Portugal) for kindly providing the anti-ErbB2 compact antibody Erb-hcAb produced by PER.C6® cells. This study was supported by AIRC (Associazione Italiana per la Ricerca sul Cancro).

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • Carmine Fedele
    • 1
  • Gennaro Riccio
    • 1
  • Angela Eliana Malara
    • 1
  • Giuseppe D’Alessio
    • 1
  • Claudia De Lorenzo
    • 1
  1. 1.Department of Structural and Functional Biology“Federico II” UniversityNaplesItaly

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