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Myocyte survival pathways and cardiomyopathy: implications for trastuzumab cardiotoxicity
1University of California San Diego, Salk Program in Molecular Medicine, University of California San Diego School of Medicine, La Jolla 92093, USA.
Abstract:
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.
Insights
Trastuzumab treats erbB-2 positive breast cancer but can cause heart failure, especially with anthracyclines. Loss of erbB-2 pathways may increase susceptibility to this cardiac toxicity.
Area of Science:
- Oncology
- Cardiology
- Molecular Biology
Background:
- Trastuzumab is effective for erbB-2 positive breast cancer.
- Cardiac failure has been observed in patients receiving trastuzumab, particularly with anthracyclines.
- Mechanisms of trastuzumab-induced cardiotoxicity are not fully understood.
Purpose of the Study:
- To review recent findings on myocyte survival pathways in heart failure.
- To explore the potential role of erbB-2 receptor-dependent pathways in trastuzumab cardiotoxicity.
- To suggest a link between genetic susceptibility and differential patient response to trastuzumab.
Main Methods:
- Review of recent clinical studies and findings on heart failure pathways.
- Analysis of potential mechanisms of drug-induced cardiotoxicity.
- Exploration of genetic factors influencing heart failure susceptibility.
Main Results:
- Myocyte survival pathways are crucial in preventing cardiomyopathy.
- Loss of erbB-2 dependent pathways may predispose patients to heart failure with anthracycline treatment.
- Individual genetic variations might explain differing susceptibilities to cardiotoxicity.
Conclusions:
- erbB-2 receptor-dependent myocyte survival pathways may be involved in trastuzumab cardiotoxicity.
- Genetic predisposition could influence the risk of developing heart failure.
- Further research is needed to elucidate the complex mechanisms of cardiotoxicity.