Antibody‐mediated inhibition of EGFR reduces phosphate excretion and induces hyperphosphatemia and mild hypomagnesemia in mice

Abstract

Monoclonal antibody therapies targeting the EGF receptor (EGFR) frequently result in hypomagnesemia in human patients. In contrast, EGFR tyrosine kinase inhibitors do not affect Mg2+ balance in patients and only have a mild effect on Mg2+ homeostasis in rodents at elevated doses. EGF has also been shown to affect phosphate (Pi) transport in rat and rabbit proximal convoluted tubules (PCT), but evidence from studies targeting EGFR and looking at Pi excretion in whole animals is still missing. Thus, the role of EGF in regulating reabsorption of Mg2+ and/or Pi in the kidney remains controversial. Here, we inject mice with the anti‐EGFR monoclonal antibody ME‐1 for 2 weeks and observe a significant increase in serum Pi and mild hypomagnesemia, but no changes in Pi or Mg2+ excretion. In contrast, a single injection of ME‐1 resulted in hyperphosphatemia and a significant reduction in Pi excretion 2 days after treatment, while no changes in serum Mg2+ or Mg2+ excretion were observed. Dietary Mg2+ deprivation is known to trigger a rapid Mg2+ conservation response in addition to hyperphosphatemia and hyperphosphaturia. Interestingly, one dose of ME‐1 did not significantly modify the response of mice to 2 days of Mg2+ deprivation. These data show that EGFR plays a significant role in regulating Pi reabsorption in the kidney PCT, but suggest only a minor role in long‐term regulation of Mg2+ transport in the distal convoluted tubule.

Targeting fibroblast growth factor 23-responsive pathways uncovers controlling genes in kidney mineral metabolism

“…Additionally, clinical studies demonstrated that patients receiving anti-epidermal growth factor receptor (EGFR) antibody therapy in trials for colorectal and other forms of cancer also J o u r n a l P r e -p r o o f demonstrate kidney magnesium wasting 29 . Previous studies showed when rodents were treated with an anti-EGFR monoclonal antibody (ME-1), they had mild, yet significantly decreased phosphate excretion, increased serum phosphate, as well as decreased serum magnesium 30 .…”

Elevated serum magnesium lowers calcification propensity in Memo1-deficient mice

“…We have previously shown that MEMO1-deficient cells are resistant to treatment with EGF [ 4 ] and FGF23 [ 2 ]. In the same line, antibody-mediated EGFR inhibition was recently shown to reduce renal phosphate excretion and concomitantly to decrease magnesemia in mice [ 29 ]. MEMO1 may thus be involved in the crosstalk between the two pathways.…”