Fibroblast Growth Factor Receptor Signaling in Cancer

Fibroblast growth factor receptors (FGFRs) are a family of transmembrane tyrosine kinases that orchestrate key cellular processes including proliferation, differentiation, survival and angiogenesis. Under normal physiology, binding of one of twenty-two fibroblast growth factors (FGFs) to an FGFR induces receptor dimerisation, autophosphorylation and activation of downstream cascades such as RAS–MAPK, PI3K–AKT and PLCγ. In cancer, FGFR signalling is frequently hijacked through gene amplifications, activating point mutations, chromosomal translocations and aberrant ligand expression. Such alterations confer a proliferative advantage, promote neo-angiogenesis and contribute to invasion, metastasis and resistance to standard therapies. Moreover, distinct FGFR family members are implicated in diverse tumour types: FGFR1 amplifications in squamous lung and breast cancers, FGFR2 fusions in intrahepatic cholangiocarcinoma, FGFR3 mutations in urothelial carcinoma and dysregulated FGF19–FGFR4 signalling in hepatocellular carcinoma. The heterogeneity of FGFR-driven tumours has spurred the development of both non-selective and highly selective small-molecule inhibitors, monoclonal antibodies and ligand traps. Despite initial clinical successes, the emergence of gatekeeper mutations, bypass signalling and intratumoural heterogeneity underlines the need for biomarkers to guide patient selection and for combination strategies to overcome resistance.

Research from Nature Portfolio

Recent clinical studies have underscored the therapeutic promise of selective FGFR inhibition in genetically defined cancers. One pivotal trial evaluated an oral FGFR1–FGFR3 inhibitor in patients with advanced solid tumours harbouring FGFR fusions or activating non-kinase-domain mutations. The study reported objective response rates of approximately 26% in fusion-positive cohorts and durable disease control in a subset of individuals without prior FGFR-targeted options. Safety profiles were consistent with anticipated on-target effects such as hyperphosphataemia and mucositis. Mechanistic analyses identified co-mutations in TP53 and BAP1 as modulators of response and revealed secondary mutations in the kinase domain that drive acquired resistance. These findings have refined selection criteria for FGFR inhibitors and illuminated pathways for next-generation drug design.

Fibroblast Growth Factor Receptor Signaling in Cancer publication trend

The graph below shows the total number of articles in fibroblast growth factor receptor signaling in cancer across all publications each year (not limited to Nature Index journals).

Technical terms

FGFR (Fibroblast Growth Factor Receptor): A receptor tyrosine kinase that binds FGFs to activate downstream signalling cascades.

Fusion: A genomic rearrangement in which a portion of an FGFR gene becomes joined to another gene, creating an oncogenic driver.

Gatekeeper Mutation: An amino acid substitution in the ATP-binding pocket of a kinase domain that reduces inhibitor binding and confers drug resistance.

Pan-FGFR Inhibitor: A small molecule that targets multiple FGFR family members, often with varying potency and off-target effects.

Ectodomain-Deficient Variant: A receptor lacking its extracellular ligand-binding domain, enabling constitutive activation of downstream pathways.

References

1. Pemigatinib in previously treated solid tumors with activating FGFR1–FGFR3 alterations: phase 2 FIGHT-207 basket trial. Nature Medicine (2024).
2. Targeting FGFR for cancer therapy. Journal of Hematology & Oncology (2024).
3. RLY-4008, the first highly selective FGFR2 inhibitor with activity across FGFR2 alterations and resistance mutations. Cancer Discovery (2023).
4. Somatic rearrangements causing oncogenic ectodomain deletions of FGFR1 in squamous cell lung cancer. Journal of Clinical Investigation (2023).
5. Fibroblast growth factor receptors in cancer: genetic alterations, diagnostics, therapeutic targets and mechanisms of resistance. British Journal of Cancer (2020).
6. Inhibitor-Sensitive FGFR1 Amplification in Human Non-Small Cell Lung Cancer. PLOS ONE (2011).
7. FGFR1 amplification in breast carcinomas: a chromogenic in situhybridisation analysis. Breast Cancer Research (2007).
8. Targeting FGFR4 Inhibits Hepatocellular Carcinoma in Preclinical Mouse Models. PLOS ONE (2012).