Myocyte survival pathways and cardiomyopathy: implications for trastuzumab cardiotoxicity.
Recent clinical studies have documented the efficacy of trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) as a new biologically targeted therapy for erbB-2 receptor-positive forms of breast cancer. During the course of a large-scale clinical trial, a subset of patients reported the onset of symptoms and signs of cardiac failure that appeared to be aggravated by concomitant exposure to anthracyclines. The mechanisms responsible for this cardiac toxicity are unclear. However, new insights into the pathways that lead to other forms of heart failure have identified a pivotal role for myocyte survival pathways in preventing the onset of cardiomyopathy and associated heart failure in genetically engineered animal models of the disease. This mini-review highlights these recent findings and suggests the possibility that the loss of erbB-2 receptor-dependent myocyte survival pathways may create a susceptibility for the onset of heart failure in response to the cardiotoxicity of anthracycline treatment. The possibility exists that the divergent susceptibility for the onset of cardiotoxicity among patients who have received trastuzumab might ultimately reflect an inherent genetic susceptibility to the diverse mechanisms that initiate, promote, and suppress the complex pathways to heart failure.
University of California San Diego, Salk Program in Molecular Medicine, University of California San Diego School of Medicine, La Jolla 92093, USA.
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D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects*; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000970:Antineoplastic Agents / Q000009:adverse effects*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D002311:Cardiomyopathy, Dilated / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D050822:Cytokine Receptor gp130; D016207:Cytokines; D018734:Genes, erbB-2; D020022:Genetic Predisposition to Disease; D006801:Humans; D006984:Hypertrophy; D008562:Membrane Glycoproteins; D020928:Mitogen-Activated Protein Kinases; D023421:Models, Animal; D009206:Myocardium / Q000166:cytology* / Q000473:pathology; D015398:Signal Transduction; D000068878:Trastuzumab; D048051:p38 Mitogen-Activated Protein Kinases
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000970:Antineoplastic Agents; D016207:Cytokines; C494199:IL6ST protein, human; D008562:Membrane Glycoproteins; D050822:Cytokine Receptor gp130; C092073:cardiotrophin 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000068878:Trastuzumab