Chronic pharmacologic inhibition of EGFR leads to cardiac dysfunction in C57BL/6J mice

Abstract

Molecule-targeted therapies like those against the epidermal growth factor receptor (EGFR) are becoming widely used in the oncology clinic. With improvements in treatment efficacy, many cancers are being treated as chronic diseases, with patients having prolonged exposure to several therapies that were previously only given acutely. The consequence of chronic suppression of EGFR activity may lead to unexpected toxicities like altered cardiac physiology, a common organ site for adverse drug effects. To explore this possibility, we treated C57BL/6J (B6) mice with two EGFR small molecule tyrosine kinase inhibitors (TKIs), irreversible EKB-569 and reversible AG-1478, orally for three months. In B6 female mice, chronic exposure to both TKIs depressed body weight gain and caused significant changes in left ventricular (LV) wall thickness and cardiac function. No significant differences were observed in heart weight or cardiomyocyte size but histological analysis revealed an increase in fibrosis and in the numbers of TUNEL-positive cells in the hearts from treated female mice. Consistent with histological results, LV apoptotic gene expression was altered, with significant downregulation of the anti-apoptotic gene Bcl2l1. Although there were no significant differences in any of these endpoints in treated male mice, suggesting sex may influence susceptibility to TKI mediated toxicity, the LVs of treated male mice had significant upregulation of Egf, Erbb2 and Nppb over controls. Taken together, these data suggest that chronic dietary exposure to TKIs may result in pathological and physiological changes in the heart.

Epidermal growth factor protects the heart against low-flow ischemia-induced injury

“…However, ErbB1 does not only have acute protective effects. It also participates in the maintenance of cardiac function [1,29]. Therefore, our results and those of previous studies indicate that like ErbB4 and ErbB2, ErbB1 has also an important role in the heart of adult animals.…”

“…However, the heart also expresses ErbB1, and EGF (necessarily through ErbB1) induces a variety of effects [4,16,28,37]. Recent evidence of the role of ErbB1 in the maintenance of cardiac function was provided by chronic administration of receptor inhibitors [1] and by a dominant negative ErbB1 mutant that was specifically induced in the heart [29]. In addition, ErbB1 protects the heart against acute stress-induced injury.…”

ErbB receptors protect the perfused heart against injury induced by epinephrine combined with low-flow ischemia

“…In addition, transactivation of ErbB1 participates in the induction of heart hypertrophy by a variety of agents (Thomas et al 2002;Shah and Catt 2003;Howes et al 2006;Forster et al 2007). Recent evidence of the role of ErbB1 in the maintenance of cardiac function was provided by chronic administration of receptor inhibitors (Barrick et al 2008) and by a dominant-negative ErbB1 mutant specifically induced in the heart (Rajagopalan et al 2008).…”

Involvement of Depressive Catecholamines as Thrombosis Risk/Inflammatory Markers in Non-Smoker, Non-Obese Congestive Heart Failure, Linked to Increased Epidermal Growth Factor-Receptor (EGF-R) Production

“…The epidermal growth factor receptor (EGF-R), also known as HER-1 or erbB-1, is the prototypical member of the family of human epithelial receptor tyrosine kinases. A wealth of evidence has established that all EGF-R/HER-1/erbB-1 family members are essential to normal CV development [3]. Currently, EGFR is considered as a convergence point in the complex signaling network and regulation of cellular functions, such as cell growth, differentiation, motility, survival and death.…”