FGF / FGFR signalling
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.
Overview
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.
In one picture
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.
Diagram
top- 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
Pages like this
not linked directly; found by shared links- TermFGFR2 fusions and rearrangements
Shares Futibatinib, Pemigatinib, FGFR2, Biliary tract cancer (cholangiocarcinoma).
- IdeactDNA-guided switching among FGFR inhibitors
Shares Futibatinib, Pemigatinib, FGFR2, Biliary tract cancer (cholangiocarcinoma).
- TrialFIGHT-202
Shares Pemigatinib, FGFR2, Biliary tract cancer (cholangiocarcinoma).
- TrialFOENIX-CCA2
Shares Futibatinib, FGFR2, Biliary tract cancer (cholangiocarcinoma).
- TrialFORTITUDE-101
Shares Bemarituzumab, FGFR2, Gastric & gastro-oesophageal junction cancer.
- TermFGFR3 alterations (bladder cancer)
Shares Erdafitinib, FGFR2, Bladder & urothelial cancer.
- TrialTHOR
Shares Erdafitinib, FGFR2, Bladder & urothelial cancer.
- CompanyTaiho Pharmaceutical (Otsuka)
Shares Futibatinib, Biliary tract cancer (cholangiocarcinoma).