Abstract
The introduction of the so-called “targeted therapies”, particularly those drugs that inhibit the activity of tyrosine kinases, has represented a remarkable progress in the treatment of cancer. Although these drugs improve survival rates in cancer, significant cardiotoxicity, manifesting as left vertricular dysfunction and/or heart failure, has emerged. The ErbB receptor tyrosine kinases are being pursued as therapeutic targets because of their important roles in normal physiology and in cancer. Besides the fact that the ErbB receptors are indispensable during development and in normal adult physiology, epidermal growth factor (EGFR) and ErbB2 in particular have been implicated in the development of many human cancers. This review focuses on the rationale for targeting members of ErbB receptor family and numerous agents that are in use for inhibiting the pathway. We summarize the current knowledge on the physiological role of ErbB signaling in the ventricle and on structural aspects of ErbB receptor activation in cancer and cardiac cells. We examine the underlying mechanisms that result in on-target or off-target cardiotoxicities of ErbB inhibitors, which can influence the design of future anticancer therapies.
Highlights
Cancer therapy has made remarkable progress with the development of “targeted therapeutics”.Whereas anthracyclines or radiotherapy are directed at all rapidly dividing cells, these therapies halt cancer cell proliferation and metastases with specific cytotoxicity
As overexpression of epidermal growth factor (EGFR) and ErbB2 receptors is often found in several human tumours such as breast, lung, head, and neck [11], ErbB receptors have been intensely pursued as therapeutic targets [8]
We will review the biology of ErbB signaling in cancer and cardiac cells, the emerging opportunities to target this system with therapeutics and we will summarize what is known of the working mechanisms of currently Food and Drug Administration (FDA) appoved ErbB targeted drugs
Summary
Cancer therapy has made remarkable progress with the development of “targeted therapeutics”. There are two general classes of ErbB-targeted therapeutics: humanized monoclonal antibodies (mAbs) directed against receptor tyrosine kinases and small-molecule tyrosine-kinase inhibitors (TKIs), targeting both receptor and nonreceptor tyrosine kinases. Many of these therapies are either in clinical use or in clinical development, several studies have revealed unanticipated side effects, including cardiotoxicities, ranging from asymptomatic LV dysfunction to symptomatic congestive heart failure (CHF) [12]. We will review the biology of ErbB signaling in cancer and cardiac cells, the emerging opportunities to target this system with therapeutics and we will summarize what is known of the working mechanisms of currently FDA appoved ErbB targeted drugs. We will focus on the underling mechanisms of these targeted therapeutics that lead to cardiotoxicity and discuss the two types of toxicity (“on- and off-target” toxicity), eludicating these mechanisms
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