EGFR Tyrosine Kinase Inhibition - Induced Cardiomyopathy

George Washington University, Washington DC

Investigators

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Abstract

DESCRIPTION (provided by applicant): Epidemiology studies have documented frequent hypomagnesemia in the elderly who also have a high cancer incidence. Anticancer drugs (eg. cisplatin, caboplatin) may cause hypomagnesemia and cardiovascular complications such as arrhythmias. EGFR inhibiting antibody (cetuximab) and TKI (erlotinib) drugs are anticancer agents, and the former is well known to produce hypomagnesemia. Recently, FDA approved-erlotinib has been reported to cause hypomagnesemia in mice, and a higher clinical incidence of gastrointestinal (GI) side effects. Our pilot study has shown significant hypomagnesemia and early systolic dysfunction in rats treated with the TKI drug, tyrphostin. Our prior animal studies demonstrated that diet-induced hypomagnesemia can trigger a significant production/release of substance P (SP) with resultant intestinal (endotoxemia) toxicity and cardiac dysfunction (decreased % FS & LVEF). Therefore, we propose that SP- induced inflammation due to hypomagnesemia may be a key mediator of the GI side effects and potential cardiovascular toxicity in some patients treated with erlotinib. The specific aims are: 1) Determine the extent of chronic erlotinib treatment-induced hypomagnesemia and subsequent intestinal and cardiac inflammation/dysfunction in rats; and 2) Assess if long-term erlotinib-induced intestinal and cardiac toxicity can be attenuated by the clinically-used SP receptor blocker, aprepitant (Emend), and if it is effective in erlotinib-treated animals with co-existing hypomagnesemia (as a paradigm for age- or Mg-wasting drug-related hypomagnesemia). Since oral Mg replacement therapy may prove ineffective in prolonged hypomagnesemia, particularly in patients with GI side effects, the outcome of this project may have immediate clinical implications for treatment of GI and potential cardiac side effects in cancer patients treated with EGFR/TKI drugs, particularly when combined with cisplatin.