# FGF / FGFR signalling

Source: https://onco.cc/pathways/fgfr-signalling/  
OnCo record `fgfr-signalling` (Pathway). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Fibroblast growth factor receptors are growth antennas on the cell surface. Bladder cancer mutates FGFR3, bile duct cancer fuses FGFR2 to other genes, and stomach cancer overproduces FGFR2b; each has its own drug, and each brings a tell-tale side effect (high phosphate) because the same receptors control phosphate in the kidney.

## Summary

Twenty-two FGF ligands bind four receptor tyrosine kinases (FGFR1-4) with heparan sulphate or, for the endocrine FGFs, with Klotho co-receptors. Dimerised receptors phosphorylate FRS2, which recruits GRB2/SOS to activate RAS-MAPK and GAB1 to activate PI3K-AKT; PLCγ and STAT branches add to the output. Oncogenic alterations: FGFR3 point mutations (S249C, Y373C) and FGFR3-TACC3 fusions in urothelial carcinoma (about 20% of advanced disease, more in upper tract); FGFR2 fusions and rearrangements in 10-15% of intrahepatic cholangiocarcinoma; FGFR2 amplification or FGFR2b overexpression in gastric cancer; FGFR1 amplification in squamous lung and luminal breast cancer. Erdafitinib (pan-FGFR) is approved for FGFR3-altered urothelial cancer after the THOR trial; pemigatinib and futibatinib (covalent, active against gatekeeper mutations) for FGFR2-fusion cholangiocarcinoma; bemarituzumab, an anti-FGFR2b antibody, is in phase 3 in gastric cancer. Hyperphosphataemia (FGF23-FGFR1 in the kidney), nail and skin changes and central serous retinopathy are class effects. Resistance arises through gatekeeper (V564) and molecular-brake mutations and through MAPK or PI3K bypass.

## Fields

- Kind: Pathway
- Last checked: 2026-09-04
- Analogy: Four aerials (FGFR1-4) tuned to growth-factor broadcasts. Bladder cancer bends an aerial so it hears a signal that is not there; bile duct cancer welds it to a foreign mast (fusion) that keeps it switched on. The inhibitors mute the aerial, but the same aerials manage phosphate in the kidney, so phosphate rises as the price.
- Interventions: Erdafitinib for FGFR3-altered advanced urothelial cancer after platinum and PD-1/PD-L1 therapy (THOR); Pemigatinib and futibatinib for FGFR2-fusion cholangiocarcinoma; futibatinib's covalent binding keeps activity against gatekeeper mutations; Bemarituzumab (anti-FGFR2b) with chemotherapy in FGFR2b-overexpressing gastric cancer (FORTITUDE-101); Phosphate binders and diet for hyperphosphataemia; eye examinations for central serous retinopathy; Selective FGFR2 and FGFR3 inhibitors under development to widen the therapeutic window

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Fibroblast_growth_factor_receptor
- Wikipedia: https://en.wikipedia.org/wiki/Fibroblast_growth_factor_receptor

## Connected records

- cancers: [Biliary tract cancer (cholangiocarcinoma)](https://onco.cc/cancers/cholangiocarcinoma/), [Bladder & urothelial cancer](https://onco.cc/cancers/urothelial/), [Gastric & gastro-oesophageal junction cancer](https://onco.cc/cancers/gastric/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- targets: [FGF23](https://onco.cc/targets/fgf23/), [FGFR1](https://onco.cc/targets/fgfr1/), [FGFR2](https://onco.cc/targets/fgfr2/), [FRS2](https://onco.cc/targets/frs2/), [GAB1](https://onco.cc/targets/gab1/), [GRB2](https://onco.cc/targets/grb2/), [KRAS](https://onco.cc/targets/kras/), [PIK3CA / PI3K-alpha](https://onco.cc/targets/pik3ca/)
- drugs: [Bemarituzumab](https://onco.cc/drugs/bemarituzumab/), [Erdafitinib](https://onco.cc/drugs/erdafitinib/), [Futibatinib](https://onco.cc/drugs/futibatinib/), [Pemigatinib](https://onco.cc/drugs/pemigatinib/)
- pathways: [Bladder cancer (KEGG map)](https://onco.cc/pathways/bladder-cancer-signalling/), [Gastric cancer (KEGG map)](https://onco.cc/pathways/gastric-cancer-signalling/), [PI3K / AKT / mTOR](https://onco.cc/pathways/pi3k-akt-mtor/), [Proteoglycans in cancer](https://onco.cc/pathways/proteoglycans-in-cancer/), [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/)
- key papers: [Androgen receptor pathway-independent prostate cancer is sustained through FGF signalling](https://onco.cc/key-papers/paper-bluemn-double-negative-prostate-fgf-mapk-cancer-cell-2017/), [Frequent and focal FGFR1 amplification associates with therapeutically tractable FGFR1 dependency in squamous cell lung cancer](https://onco.cc/key-papers/paper-weiss-fgfr1-amplification-squamous-lung-sci-transl-med-2010/)

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