Mechanisms of cardiotoxicity associated with ErbB2 inhibitors.
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.
Department of Structural and Functional Biology, "Federico II" University, Via Cinthia, 80126 Naples, Italy.
Carmine
C
Fedele
Gennaro
G
Riccio
Angela Eliana
AE
Malara
Giuseppe
G
D'Alessio
Claudia
C
De Lorenzo
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology* / Q000633:toxicity; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D000077341:Lapatinib; D020935:MAP Kinase Signaling System; D032386:Myoblasts, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D011485:Protein Binding; D000090063:Proto-Oncogene Mas; D011799:Quinazolines / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D066247:Receptor, ErbB-4; D000068878:Trastuzumab
D061067:Antibodies, Monoclonal, Humanized; D066246:ErbB Receptors; D000077341:Lapatinib; D000090063:Proto-Oncogene Mas; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D066247:Receptor, ErbB-4; D000068878:Trastuzumab; C000715470:MAS1 protein, human; C508053:ERBB2 protein, human; C587689:ERBB4 protein, human; C587690:Erbb4 protein, mouse; C587691:Erbb4 protein, rat; C485206:pertuzumab