title: Pan-FGFR inhibition leads to blockade of FGF23 signaling, soft tissue mineralization, and cardiovascular dysfunction.
abstract: 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.
authors.affiliation: * Drug Safety Research & Development, and.
authors.forename: Gina M
authors.initials: GM
authors.lastname: Yanochko
authors.forename: Allison
authors.initials: A
authors.lastname: Vitsky
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Heyen
authors.forename: Brad
authors.initials: B
authors.lastname: Hirakawa
authors.forename: Justine L
authors.initials: JL
authors.lastname: Lam
authors.forename: Jeff
authors.initials: J
authors.lastname: May
authors.forename: Tim
authors.initials: T
authors.lastname: Nichols
authors.forename: Frederick
authors.initials: F
authors.lastname: Sace
authors.forename: Dusko
authors.initials: D
authors.lastname: Trajkovic
authors.forename: Eileen
authors.initials: E
authors.lastname: Blasi
mesh_terms: D000818:Animals; D001483:Base Sequence; D002319:Cardiovascular System / Q000378:metabolism / Q000503:physiopathology*; D002460:Cell Line; D017931:DNA Primers; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction
chemical_list: D017931:DNA Primers; C000717427:FGF23 protein, human; C505605:Fgf23 protein, rat; D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23
keywords: fibroblast growth factor receptor; fibroblast growth factor-23; klotho; mineralization; phosphate; vitamin D.