Fibroblast Growth Factor Receptor

1. FGFR Overview

• Full Name: Fibroblast Growth Factor Receptor
• Type: Receptor tyrosine kinase
• Family Members: FGFR1, FGFR2, FGFR3, FGFR4
• Normal Function:
  • Binds FGFs (fibroblast growth factors) → activates intracellular signaling
  • Regulates cell proliferation, differentiation, survival, migration, and angiogenesis

2. FGFR Signaling Pathway

• FGFR activation → autophosphorylation → triggers downstream pathways:
  • RAS–RAF–MEK–ERK → proliferation
  • PI3K–AKT–mTOR → survival
  • STAT pathway → differentiation and migration

3. Oncogenic FGFR Alterations

• Mutations: Point mutations in FGFR genes → constitutive activation
• Fusions / Translocations: e.g., FGFR3-TACC3 fusion in bladder cancer
• Amplifications / Overexpression: FGFR1 amplification in breast and lung cancers

Cancer Types Commonly Associated

4. FGFR Inhibitors

• Small molecule TKIs targeting FGFR:
  • Erdafitinib – FDA approved for FGFR3-mutant urothelial carcinoma
  • Pemigatinib – FDA approved for FGFR2 fusion/rearranged cholangiocarcinoma
  • Infigratinib – FGFR2/3 targeted
• Mechanism: Blocks FGFR kinase activity → inhibits downstream signaling

Key Points:

• Requires molecular testing to detect FGFR mutations/fusions.
• Resistance may occur via secondary mutations or activation of bypass pathways.

5. Adverse Effects of FGFR Inhibitors

Clinical Summary:

• FGFR alterations are actionable targets in precision oncology.
• FGFR inhibitors are mutation/fusion-specific therapies, mostly for bladder, cholangiocarcinoma, and selected lung or gastric cancers.
• Testing is mandatory because only patients with FGFR alterations benefit.