title: 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 3 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.
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Cordelia J
authors.initials: CJ
authors.lastname: Barrick
authors.forename: Ming
authors.initials: M
authors.lastname: Yu
authors.forename: Hann-Hsiang
authors.initials: HH
authors.lastname: Chao
authors.forename: David W
authors.initials: DW
authors.lastname: Threadgill
mesh_terms: D000634:Aminoquinolines; D000814:Aniline Compounds; D000818:Animals; D001021:Aortic Valve / Q000187:drug effects / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009930:Organic Chemicals / Q000633:toxicity*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D011799:Quinazolines; D012727:Sex Characteristics; D020032:Tyrphostins / Q000633:toxicity*
chemical_list: D000634:Aminoquinolines; D000814:Aniline Compounds; D009930:Organic Chemicals; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D066246:ErbB Receptors; C413879:EKB 569