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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.
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.
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.
It shows that leaving androgen receptor dependence does not have to mean becoming neuroendocrine, and it names a treatable pathway for a group of men whose tumours would otherwise be described only by what they lack.
It was the first therapeutically tractable alteration found in squamous lung cancer, and in the decade since it has become the standard example of amplification not equalling dependence, because copy number alone has selected patients poorly in trials.
Shares Futibatinib, Pemigatinib, FGFR2, Biliary tract cancer (cholangiocarcinoma).
Shares Futibatinib, Pemigatinib, FGFR2, Biliary tract cancer (cholangiocarcinoma).
Shares Bemarituzumab, FGFR2, Gastric & gastro-oesophageal junction cancer.
Shares Futibatinib, Pemigatinib, FGFR2, Biliary tract cancer (cholangiocarcinoma).
Shares GRB2, PIK3CA / PI3K-alpha, PI3K / AKT / mTOR, RAS / RAF / MEK / ERK (MAPK).
Shares Erdafitinib, FGFR2, PIK3CA / PI3K-alpha, KRAS.
Shares Erdafitinib, FGFR2, Bladder & urothelial cancer.
Shares Futibatinib, FGFR2, Biliary tract cancer (cholangiocarcinoma).