{"entity":{"id":"fgfr-signalling","kind":"pathway","name":"FGF / FGFR signalling","aka":[],"tldr":"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.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Fibroblast_growth_factor_receptor","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Fibroblast_growth_factor_receptor"}],"tags":[],"related":[],"cancers":["urothelial","cholangiocarcinoma","gastric"],"sections":[],"technologies":[],"targets":["fgfr2","kras","pik3ca"],"drugs":["erdafitinib","pemigatinib","futibatinib","bemarituzumab"],"companies":[],"institutions":[],"pathways":["ras-mapk","pi3k-akt-mtor"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"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.","nodes":[{"id":"fgf","label":"FGF ligands (+ heparan sulphate / Klotho)","x":50,"y":5},{"id":"fgfr","label":"FGFR1-4 (FGFR2 fusions, FGFR3 mutations)","x":50,"y":24,"targetId":"fgfr2"},{"id":"frs2","label":"FRS2","x":50,"y":42},{"id":"ras","label":"GRB2 / SOS → RAS → MAPK","x":22,"y":62,"targetId":"kras"},{"id":"pi3k","label":"GAB1 → PI3K → AKT","x":50,"y":62,"targetId":"pik3ca"},{"id":"plc","label":"PLCγ / STAT","x":78,"y":62},{"id":"out","label":"Proliferation, survival, angiogenesis","x":50,"y":88},{"id":"phos","label":"FGF23 → FGFR1 (kidney phosphate; drug side effect)","x":84,"y":24}],"edges":[{"from":"fgf","to":"fgfr","type":"activates"},{"from":"fgfr","to":"frs2","type":"activates"},{"from":"frs2","to":"ras","type":"activates"},{"from":"frs2","to":"pi3k","type":"activates"},{"from":"fgfr","to":"plc","type":"activates"},{"from":"ras","to":"out","type":"activates"},{"from":"pi3k","to":"out","type":"activates"},{"from":"plc","to":"out","type":"activates"},{"from":"phos","to":"fgfr","type":"activates"}],"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"]},"route":"/pathways/fgfr-signalling/","neighbours":{"cancer":[{"id":"cholangiocarcinoma","kind":"cancer","name":"Biliary tract cancer (cholangiocarcinoma)","route":"/cancers/cholangiocarcinoma/"},{"id":"urothelial","kind":"cancer","name":"Bladder & urothelial cancer","route":"/cancers/urothelial/"},{"id":"gastric","kind":"cancer","name":"Gastric & gastro-oesophageal junction cancer","route":"/cancers/gastric/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}],"target":[{"id":"fgf23","kind":"target","name":"FGF23","route":"/targets/fgf23/"},{"id":"fgfr1","kind":"target","name":"FGFR1","route":"/targets/fgfr1/"},{"id":"fgfr2","kind":"target","name":"FGFR2","route":"/targets/fgfr2/"},{"id":"frs2","kind":"target","name":"FRS2","route":"/targets/frs2/"},{"id":"gab1","kind":"target","name":"GAB1","route":"/targets/gab1/"},{"id":"grb2","kind":"target","name":"GRB2","route":"/targets/grb2/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"},{"id":"pik3ca","kind":"target","name":"PIK3CA / PI3K-alpha","route":"/targets/pik3ca/"}],"drug":[{"id":"bemarituzumab","kind":"drug","name":"Bemarituzumab","route":"/drugs/bemarituzumab/"},{"id":"erdafitinib","kind":"drug","name":"Erdafitinib","route":"/drugs/erdafitinib/"},{"id":"futibatinib","kind":"drug","name":"Futibatinib","route":"/drugs/futibatinib/"},{"id":"pemigatinib","kind":"drug","name":"Pemigatinib","route":"/drugs/pemigatinib/"}],"pathway":[{"id":"bladder-cancer-signalling","kind":"pathway","name":"Bladder cancer (KEGG map)","route":"/pathways/bladder-cancer-signalling/"},{"id":"gastric-cancer-signalling","kind":"pathway","name":"Gastric cancer (KEGG map)","route":"/pathways/gastric-cancer-signalling/"},{"id":"pi3k-akt-mtor","kind":"pathway","name":"PI3K / AKT / mTOR","route":"/pathways/pi3k-akt-mtor/"},{"id":"proteoglycans-in-cancer","kind":"pathway","name":"Proteoglycans in cancer","route":"/pathways/proteoglycans-in-cancer/"},{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"}],"paper":[{"id":"paper-bluemn-double-negative-prostate-fgf-mapk-cancer-cell-2017","kind":"paper","name":"Androgen receptor pathway-independent prostate cancer is sustained through FGF signalling","route":"/key-papers/paper-bluemn-double-negative-prostate-fgf-mapk-cancer-cell-2017/"},{"id":"paper-weiss-fgfr1-amplification-squamous-lung-sci-transl-med-2010","kind":"paper","name":"Frequent and focal FGFR1 amplification associates with therapeutically tractable FGFR1 dependency in squamous cell lung cancer","route":"/key-papers/paper-weiss-fgfr1-amplification-squamous-lung-sci-transl-med-2010/"}]}}