Effects of the EGFR inhibitor erlotinib on magnesium handling

Abstract

A mutation in pro-EGF causes isolated hypomagnesemia, and monoclonal antibodies targeting the extracellular domain of the EGF receptor (EGFR) affect epithelial Mg2+ transport. The effect of the EGFR tyrosine kinase inhibitor erlotinib on Mg2+ homeostasis, however, remains unknown. Here, we injected C57BL/6 mice with erlotinib for 23 days and observed a small but significant decrease in serum Mg2+ concentrations at days 16 and 23, but the fractional excretion of Mg2+ remained unchanged after 23 days. Semiquantitative immunohistochemical evaluation did not reveal detectable changes in renal expression of transient receptor potential melastatin 6 (TRPM6) protein, the channel that mediates Mg2+ reabsorption. Patch clamp analysis in TRPM6-expressing cells demonstrated that 30 μM erlotinib inhibited EGF-induced changes in TRPM6 current density and tyrosine phosphorylation of EGFR; 0.3 μM erlotinib did not have these effects. Furthermore, 30 μM erlotinib inhibited EGF-stimulated increases in the mobile fraction of endomembrane TRPM6 channels. In summary, erlotinib can influence Mg2+ handling but its effect on the systemic Mg2+ concentration seems less potent than that observed with antibody-based EGFR inhibitors. These data suggest that typical human dosages of erlotinib are unlikely to severely affect serum Mg2+ concentrations. Copyright © 2010 by the American Society of Nephrology.