Pan-FGFR inhibition leads to blockade of FGF23 signaling, soft tissue mineralization, and cardiovascular dysfunction

The fibroblast growth factor receptors (FGFR) play a major role in angiogenesis and are desirable targets for the development of therapeutics. Groups of Wistar Han rats were dosed orally once daily for 4 days with a small molecule pan-FGFR inhibitor (5mg/kg) or once daily for 6 days with a small mol...

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Bibliographic Details
Published in:Toxicological sciences 2013-10, Vol.135 (2), p.451-464
Main Authors: Yanochko, Gina M, Vitsky, Allison, Heyen, Jonathan R, Hirakawa, Brad, Lam, Justine L, May, Jeff, Nichols, Tim, Sace, Frederick, Trajkovic, Dusko, Blasi, Eileen
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Cardiovascular System - metabolism
Cardiovascular System - physiopathology
Cell Line
DNA Primers
Fibroblast Growth Factors - metabolism
Humans
Phosphorylation
Rats
Rats, Wistar
Receptors, Fibroblast Growth Factor - antagonists & inhibitors
Signal Transduction
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Summary:The fibroblast growth factor receptors (FGFR) play a major role in angiogenesis and are desirable targets for the development of therapeutics. Groups of Wistar Han rats were dosed orally once daily for 4 days with a small molecule pan-FGFR inhibitor (5mg/kg) or once daily for 6 days with a small molecule MEK inhibitor (3mg/kg). Serum phosphorous and FGF23 levels increased in all rats during the course of the study. Histologically, rats dosed with either drug exhibited multifocal, multiorgan soft tissue mineralization. Expression levels of the sodium phosphate transporter Npt2a and the vitamin D-metabolizing enzymes Cyp24a1 and Cyp27b1 were modulated in kidneys of animals dosed with the pan-FGFR inhibitor. Both inhibitors decreased ERK phosphorylation in the kidneys and inhibited FGF23-induced ERK phosphorylation in vitro in a dose-dependent manner. A separate cardiovascular outcome study was performed to monitor hemodynamics and cardiac structure and function of telemetered rats dosed with either the pan-FGFR inhibitor or MEK inhibitor for 3 days. Both compounds increased blood pressure (~+ 17 mmHg), decreased heart rate (~-75 bpm), and modulated echocardiography parameters. Our data suggest that inhibition of FGFR signaling following administration of either pan-FGFR inhibitor or MEK inhibitor interferes with the FGF23 pathway, predisposing animals to hyperphosphatemia and a tumoral calcinosis-like syndrome in rodents.
ISSN:1096-6080
1096-0929
DOI:10.1093/toxsci/kft161