Epidermal growth factor receptor‐tyrosine kinase inhibition by erlotinib causes hypomagnesemia, oxidative stress and cardiac dysfunction

Abstract

We assessed cardiac dysfunction using endocardiography in rats treated with the anticancer drug erlotinib (Tarceva) at a dose of 10 mg/kg/day over a 9 week period. We observed significant progressive hypomagnesemia (P<0.05) at 5 and 9 weeks, when a 3‐fold elevation (P<0.05) of neutrophil superoxide production was seen. Moderately decreased (P<0.05) cardiac LV ejection fraction and % fractional shortening were measured at 7 weeks, and diastolic dysfunction (lower mitral valve E/A ratio) achieved significance (P<0.05) at 9 weeks of erlotinib treatment. Our prior studies with another EGFR‐TKI agent, tyrphostin AG1478 (21 mg/kg/day), also showed similar hypomagnesemia, oxidative stress, elevated plasma substance P and cardiac dysfunction after 5 weeks of treatment (Can. J. Physiol. Pharmacol. 90:1145–1149, 2012). Clinical studies have documented persistent hypomagnesemia in cancer patients treated with cetuximab (EGFR‐blocking antibody). We conclude that EGFR‐TK inhibiting agents also cause hypomagnesemia; in addition, oxidative stress and impaired cardiac contractility also occur in our rodent model. The clinical relevance of these findings with the increasing use of EGFR‐TK inhibiting drugs remains to be determined.