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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

Abstract

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.

Keywords

ErbB2/Her2 Cancer therapy Cardiotoxicity Herceptin/trastuzumab Lapatinib 

Abbreviations

HFC

Human fetal cardiomyocytes

scFv

Single chain fragment variable

Erb-hcAb

Erbicin-human-compact antibody

NRG-1

Neuregulin 1β

Notes

Acknowledgments

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.

References

  1. 1.
    Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/Neu oncogene. Science 235(4785):177–182PubMedCrossRefGoogle Scholar
  2. 2.
    Baselga J, Albanell J, Molina MA, Arribas J (2001) Mechanism of action of trastuzumab and scientific update. Semin Oncol 28:4–11PubMedCrossRefGoogle Scholar
  3. 3.
    Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792PubMedCrossRefGoogle Scholar
  4. 4.
    Sparano JA (2001) Cardiac toxicity of trastuzumab (herceptin): implications for the design of adjuvant trials. Semin Oncol 28:20–27. doi: 10.1053/sonc.2001.22813 PubMedCrossRefGoogle Scholar
  5. 5.
    Chien KR (2000) Myocyte survival pathways and cardiomyopathy: implications for trastuzumab cardiotoxicity. Semin Oncol 27:9–14 (discussion 92–100)PubMedGoogle Scholar
  6. 6.
    Crone SA, Zhao YY, Fan L, Gu Y, Minamisawa S, Liu Y, Peterson KL, Chen J, Kahn R, Condorelli G, Ross J Jr, Chien KR, Lee KF (2002) ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med 8:459–465. doi: 10.1038/nm0502-459 PubMedCrossRefGoogle Scholar
  7. 7.
    Force T, Krause DS, Van Etten RA (2007) Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer 7:332–344. doi: 10.1038/nrc2106 PubMedCrossRefGoogle Scholar
  8. 8.
    Agus DB, Gordon MS, Taylor C, Natale RB, Karlan B, Mendelson DS, Press MF, Allison DE, Sliwkowski MX, Lieberman G, Kelsey SM, Fyfe G (2005) Phase I clinical study of pertuzumab, a novel HER dimerization inhibitor, in patients with advanced cancer. J Clin Oncol 23:2534–2543. doi: 10.1200/JCO.2005.03.184 PubMedCrossRefGoogle Scholar
  9. 9.
    Burris HA 3rd, Hurwitz HI, Dees EC, Dowlati A, Blackwell KL, O’Neil B, Marcom PK, Ellis MJ, Overmoyer B, Jones SF, Harris JL, Smith DA, Koch KM, Stead A, Mangum S, Spector NL (2005) Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. J Clin Oncol 23:5305–5313. doi: 10.1200/JCO.2005.16.584 PubMedCrossRefGoogle Scholar
  10. 10.
    Perez EA, Koehler M, Byrne J, Preston AJ, Rappold E, Ewer MS (2008) Cardiac safety of lapatinib: pooled analysis of 3689 patients enrolled in clinical trials. Mayo Clinic Proc 83:679–686Google Scholar
  11. 11.
    Fedele C, Riccio G, Coppola C, Barbieri A, Monti MG, Arra C, Tocchetti CG, D’Alessio G, Maurea N, De Lorenzo C (2011) Comparison of preclinical cardiotoxic effects of different ErbB2 inhibitors. Breast Cancer Res Treat. doi: 10.1007/s10549-011-1783-9
  12. 12.
    De Lorenzo C, Palmer DB, Piccoli R, Ritter MA, D’Alessio G (2002) A new human antitumor immunoreagent specific for ErbB2. Clin Cancer Res 8:1710–1719PubMedGoogle Scholar
  13. 13.
    De Lorenzo C, Tedesco A, Terrazzano G, Cozzolino R, Laccetti P, Piccoli R, D’Alessio G (2004) A human, compact, fully functional anti-ErbB2 antibody as a novel antitumour agent. Br J Cancer 91:1200–1204. doi: 10.1038/sj.bjc.6602110 PubMedGoogle Scholar
  14. 14.
    De Lorenzo C, Cozzolino R, Carpentieri A, Pucci P, Laccetti P, D’Alessio G (2005) Biological properties of a human compact anti-ErbB2 antibody. Carcinogenesis 26:1890–1895. doi: 10.1093/carcin/bgi146 PubMedCrossRefGoogle Scholar
  15. 15.
    De Lorenzo C, Troise F, Cafaro V, D’Alessio G (2007) Combinatorial experimental protocols for erbicin-derived immunoagents and herceptin. Br J Cancer 97:1354–1360. doi: 10.1038/sj.bjc.6604022 PubMedCrossRefGoogle Scholar
  16. 16.
    Troise F, Monti M, Merlino A, Cozzolino F, Fedele C, Russo Krauss I, Sica F, Pucci P, D’Alessio G, De Lorenzo C (2011) A novel ErbB2 epitope targeted by human antitumor immunoagents. FEBS J 278:1156–1166. doi: 10.1111/j.1742-4658.2011.08041.x PubMedCrossRefGoogle Scholar
  17. 17.
    Riccio G, Esposito G, Leoncini E, Contu R, Condorelli G, Chiariello M, Laccetti P, Hrelia S, D’Alessio G, De Lorenzo C (2009) Cardiotoxic effects, or lack thereof, of anti-ErbB2 immunoagents. FASEB J 23:3171–3178. doi: 10.1096/fj.09-131383 PubMedCrossRefGoogle Scholar
  18. 18.
    Daly JM, Jannot CB, Beerli RR, Graus-Porta D, Maurer FG, Hynes NE (1997) Neu differentiation factor induces ErbB2 down-regulation and apoptosis of ErbB2-overexpressing breast tumor cells. Cancer Res 57:3804–3811PubMedGoogle Scholar
  19. 19.
    Fendly BM, Winget M, Hudziak RM, Lipari MT, Napier MA, Ullrich A (1990) Characterization of murine monoclonal antibodies reactive to either the human epidermal growth factor receptor or HER2/Neu gene product. Cancer Res 50:1550–1558PubMedGoogle Scholar
  20. 20.
    Kuramochi Y, Guo X, Sawyer DB (2006) Neuregulin activates erbB2-dependent src/FAK signaling and cytoskeletal remodeling in isolated adult rat cardiac myocytes. J Mol Cell Cardiol 41:228–235PubMedCrossRefGoogle Scholar
  21. 21.
    Gassmann M, Casagranda F, Orioli D, Simon H, Lai C, Klein R, Lemke G (1995) Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Nature 378:390–394PubMedCrossRefGoogle Scholar
  22. 22.
    Lee KF, Simon H, Chen H, Bates B, Hung MC, Hauser C (1995) Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature 378:394–398PubMedCrossRefGoogle Scholar
  23. 23.
    Meyer D, Birchmeier C (1995) Multiple essential functions of neuregulin in development. Nature 378:386–390PubMedCrossRefGoogle Scholar
  24. 24.
    Zhao YY, Sawyer DR, Baliga RR, Opel DJ, Han X, Marchionni MA, Kelly RA (1998) Neuregulins promote survival and growth of cardiac myocytes. Persistence of ErbB2 and ErbB4 expression in neonatal and adult ventricular myocytes. J Biol Chem 273:10261–10269PubMedCrossRefGoogle Scholar
  25. 25.
    Pinkas-Kramarski R, Soussan L, Waterman H, Levkowitz G, Alroy I, Klapper L, Lavi S, Seger R, Ratzkin BJ, Sela M, Yarden Y (1996) Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions. EMBO J 15:2452–2467PubMedGoogle Scholar
  26. 26.
    Yarden Y, Sliwkowski MX (2001) Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2:127–137PubMedCrossRefGoogle Scholar
  27. 27.
    Fuller SJ, Sivarajah K, Sugden PH (2008) ErbB receptors, their ligands, and the consequences of their activation and inhibition in the myocardium. J Mol Cell Cardiol 44:831–854PubMedCrossRefGoogle Scholar
  28. 28.
    Bersell K, Arab S, Haring B, Kuhn B (2009) Neuregulin1/ErbB4 signaling induces cardiomyocyte proliferation and repair of heart injury. Cell 138:257–270PubMedCrossRefGoogle Scholar
  29. 29.
    De Keulenaer GW, Doggen K, Lemmens K (2010) The vulnerability of the heart as a pluricellular paracrine organ: lessons from unexpected triggers of heart failure in targeted ErbB2 anticancer therapy. Circ Res 106:35–46PubMedCrossRefGoogle Scholar

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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