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Pan-FGFR inhibition leads to blockade of FGF23 signaling, soft tissue mineralization, and cardiovascular dysfunction
Gina M Yanochko1, Allison Vitsky, Jonathan R Heyen
1* Drug Safety Research & Development, and.
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.
Insights
Fibroblast growth factor receptor (FGFR) and MEK inhibitors disrupt the FGF23 pathway, leading to hyperphosphatemia and mineralization in rodents. This suggests potential risks associated with targeting these signaling pathways.
Area of Science:
- Pharmacology
- Biochemistry
- Toxicology
Background:
- Fibroblast growth factor receptors (FGFR) are crucial for angiogenesis and represent therapeutic targets.
- Dysregulation of FGFR signaling can impact various physiological processes.
Purpose of the Study:
- To investigate the effects of a pan-FGFR inhibitor and a MEK inhibitor on the FGF23 pathway and associated physiological parameters in rats.
- To evaluate the potential for hyperphosphatemia and mineralization following inhibition of FGFR or MEK signaling.
Main Methods:
- Wistar Han rats were administered pan-FGFR or MEK inhibitors orally.
- Serum phosphorous and FGF23 levels were monitored.
- Histopathological analysis assessed soft tissue mineralization.
- Kidney gene expression and ERK phosphorylation were analyzed.
- Cardiovascular parameters were monitored in a separate study.
Main Results:
- Both inhibitors increased serum phosphorous and FGF23 levels.
- Multifocal, multiorgan soft tissue mineralization was observed.
- Kidney transporter and enzyme expression was modulated by the pan-FGFR inhibitor.
- ERK phosphorylation was decreased in kidneys and inhibited FGF23-induced phosphorylation in vitro.
- Cardiovascular studies showed increased blood pressure and decreased heart rate.
Conclusions:
- Inhibition of FGFR or MEK signaling interferes with the FGF23 pathway.
- This interference can lead to hyperphosphatemia and a tumoral calcinosis-like syndrome in rodents.
- These findings highlight potential toxicological concerns for FGFR and MEK inhibitors.
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