FGFR

  • Fibroblast growth factor receptor (FGFR)
  • Gene location(s):
    • FGFR1 occurs the most frequently in pancreatic ductal adenocarcinoma (PDAC); found on chromosome 8 (8p11.23)
    • FGFR2—chromosome 10 (10q26.13)
    • FGFR3— chromosome 4 (4p16.3)
    • FGFR4— chromosome 5 (5q35.2)

FGFR Biology

  • The FGFR signaling pathway regulates critical cellular processes: cell proliferation, differentiation, apoptosis, angiogenesis, and tissue repair. Aberrant FGFR signaling contributes to tumorigenesis, invasion, and metastasis in multiple cancers, including PDAC.1
  • The FGFR family consists of 4 main receptor tyrosine kinases: FGFR1, FGFR2, FGFR3, and FGFR4, with multiple splice isoforms affecting ligand binding and signaling specificity.2
  • Binding of FGFs (ligands) to FGFRs induces receptor dimerization and activation of the intracellular tyrosine kinase domain, leading to phosphorylation of tyrosine residues that serve as docking sites for downstream signaling adaptors.3
  • Key downstream signaling pathways activated by FGFR include4:
    • the RAS-MAPK pathway (regulates proliferation and differentiation)
    • the PI3K-AKT pathway (cell survival and metabolism)
    • the STAT pathway (transcriptional regulation).
  • Overactivation of FGFR signaling due to mutations, amplifications, or ligand overexpression leads to uncontrolled cellular proliferation and survival, contributing to oncogenesis.5

Etiology & Epidemiology

  • FGFR1 overexpression/amplification occurs in approximately 10% of advanced PDAC cases and is correlated with poor prognosis and aggressive tumor biology. Early-stage PDAC shows FGFR1 alterations less frequently (≈4% to 5%).6
  • FGFR gene amplification and mutations often arise from chromosomal copy number gains, particularly affecting FGFR1 and FGFR2 loci and leading to ligand-independent receptor activation.7
  • Tumor microenvironment factors, such as hypoxia, can also induce FGFR pathway upregulation as an adaptive survival mechanism in PDAC.8
  • While hereditary cancer syndromes like Lynch syndrome and Peutz-Jeghers syndrome do not directly cause FGFR amplification, their associated genomic instability may contribute to oncogenic FGFR alterations in some tumors.9,10

Testing

When to Test11-12:

  • Because FGFR alterations (amplifications, fusions, mutations) are relatively rare in PDAC, routine FGFR testing is not widespread and is generally reserved for select cases where targeted FGFR inhibitors are considered or within clinical trials.
  • Testing is more frequently considered in patients with KRAS wild-type tumors, which are more likely to harbor alternative drivers such as FGFR fusions or other actionable mutations.

Testing Methods13-16:

  • Immunohistochemistry (IHC) detects the presence and level of FGFR proteins in formalin-fixed, paraffin-embedded tumor tissue. Using tumor tissue samples from biopsies, IHC testing can identify FGFR overexpression (via protein expression) and is commonly used for initial screening.
  • Fluorescence in situ hybridization (FISH) is typically conducted following IHC results to confirm gene amplification and confirm the results of IHC testing. FISH can directly detect gene amplification by determining copy number gain and providing more numerical data.

Guideline Recommendations14-16:

  • Major clinical guidelines (NCCN, European Society for Molecular Oncology, American Society of Clinical Oncology) currently do not recommend routine FGFR testing in PDAC outside clinical trials or specific contexts, such as KRAS wild-type metastatic cases.
  • FGFR testing is typically performed in clinical trial settings or when considering targeted FGFR inhibitors in cancers with higher FGFR alteration prevalence (eg, cholangiocarcinoma, bladder cancer).
  • In PDAC, testing is mostly considered for metastatic tumors or when broad molecular profiling is done to identify rare actionable alterations.

Targeted Therapy

FDA-Approved Agents:

  • As of mid-2025, there are no targeted therapies with approved indications specific for treating PDAC with FGFR alterations.

Investigational Agents:

  • Pemigatinib17
    • On April 17, 2020, pemigatinib received accelerated approval by the FDA for the treatment of adults with previously treated, locally advanced bile duct cancer However, it is not yet FDA approved in pancreatic cancer and is undergoing clinical trials (eg, FIGHT-302).
    • Mechanism of action18,19:
      • Pemigatinib is an oral, selective inhibitor of FGFR1, FGFR2, and FGFR3  that has been approved for cholangiocarcinoma but that is being tested for other cancers with FGFR alterations (eg, pancreatic cancer).
      • Pemigatinib is designed to bind to the ATP-binding pocket of FGFR1, FGFR2, and FGFR3, acting as a noncompetitive inhibitor that blocks kinase activity and halts autophosphorylation of downstream receptors.
      • Blocking these pathways allows pemigatinib to reduce tumor cell proliferation and induce apoptosis, restabilizing the uncontrolled proliferation caused by FGFR overamplification.
      • Some tumors with FGFR2 fusions or rearrangements are especially susceptible to FGFR inhibition, making pemigatinib and other FGFR inhibitors significantly more effective in treatment.
  • Erdafitinib20
    • Erdafinitib received full FDA approval on January 19, 2024, enabling its use in patients with metastatic urothelial carcinoma and susceptible FGFR3 genetic alterations. However, it is still being studied for use in pancreatic cancer.
    • Mechanism of action21:
      • Erdafitinib is an oral pan-FGFR inhibitor that targets the activity of FGFR1, FGFR2, FGFR3, and FGFR4. It is generally less selective than pemigatinib, targeting a broader spectrum of FGFR receptors.
      • It serves as a reversible ATP-competitive inhibitor of the intracellular kinase domain of FGFR1, FGFR2, FGFR3, and FGFR4, preventing ATP from initiating the phosphorylation cascade that enables downstream signaling.
      • Inhibiting autophosphorylation of FGFR shuts down the MAPK, PI3K-AKT, and PLCγ pathways, disabling cell proliferation, inducing apoptosis, and affecting cell motility.
      • Erdafitinib uses phosphate levels as a biomarker due to the involvement of FGFR in phosphate homeostasis through FGF23 signaling. Increased blood phosphate levels caused by FGFR inhibition indicate effective treatment, allowing for personalized dosage under controlled monitoring.

References

  1. Kang X, Lin Z, Xu M, Pan J, Wang ZW. Deciphering role of FGFR signalling pathway in pancreatic cancer. CellProlif. 2019;52(3):e12605. doi:10.1111/cpr.12605
  2. Liu Q, Huang J, Yan W, Liu Z, Liu S, Fang W. FGFR families: biological functions and therapeutic interventions in tumors. MedComm (2020). 2023;4(5):e367. doi:10.1002/mco2.367
  3. FGFR signaling pathway. Danaher Life Sciences.  2020. Accessed July 9, 2025. https://lifesciences.danaher.com/us/en/library/fgf-pathway.html
  4. Du S, Zhang Y, Xu J. Current progress in cancer treatment by targeting FGFR signaling. CancerBiol andMed . 2023;20(7):490-499. doi:10.20892/j.issn.2095-3941.2023.0137
  5. Orlandi E, Guasconi M, Vecchia S, et al. Exploring the horizon: anti-fibroblast growth factor receptor therapy in pancreatic cancer with aberrant fibroblast growth factor receptor expression—a scoping review. Cancers. 2024;16(16):2912. doi:10.3390/cancers16162912
  6. Haq F, Sung YN, Park I, et al. FGFR1 expression defines clinically distinct subtypes in pancreatic cancer. JTransl Med. 2018;16(1):374. doi:10.1186/s12967-018-1743-9
  7. Bailey P, Chang D, Nones K, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531:47-52. doi:10.1038/nature16965
  8. Blick C, Ramachandran A, Wigfield S, et al. Hypoxia regulates FGFR3 expression via HIF-1α and miR-100 and contributes to cell survival in non-muscle invasive bladder cancer. Br J Cancer. 2013;109(1):50-59. doi:10.1038/bjc.2013.240
  9. Kastrinos F, Mukherjee B, Tayob N, et al. Risk of pancreatic cancer in families with Lynch syndrome. JAMA. 2009;302(16):1790-1795. doi:10.1001/jama.2009.1529
  10. Korsse SE, Harinck F, van Lier MG, et al. Pancreatic cancer risk in Peutz-Jeghers syndrome patients: a large cohort study and implications for surveillance. J Med Genet. 2013;50(1):59-64. doi:10.1136/jmedgenet-2012-101277
  11. Singhi AD, George B, Greenbowe JR, et al. Real-time targeted genome profile analysis of pancreatic ductal adenocarcinomas identifies genetic alterations that might be targeted with existing drugs or used as biomarkers. Gastroenterology. 2019;156(8):2242-2253.e4. doi:10.1053/j.gastro.2019.02.037
  12. Perera RM, Wang J, Kanchi KL, et al. Molecular profiling for pancreatic cancer: current practice and guidelines. J Clin Oncol. 2024;42(12):1240-1253. doi:10.1200/JCO.23.02019
  13. Wang H, Lu J, Tang J, Chen S, He K, Jiang X, Jiang W, Teng L. Establishment of patient-derived gastric cancer xenografts: a useful tool for preclinical evaluation of targeted therapies involving alterations in HER-2, MET and FGFR2 signaling pathways. BMC Cancer. 2017;17(1):191. doi:10.1186/s12885-017-3177-9
  14. NCCN. Clinical Practice Guidelines in Oncology. Pancreatic adenocarcinoma, version 2.2025. Accessed July 9, 2025. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf
  15. Clinical practice guidelines: pancreatic cancer. European Society for Medical Oncology. 2024. Accessed July 9, 2025. https://www.esmo.org/guidelines/gastrointestinal-cancers/pancreatic-cancer
  16. ASCO Expert Panel. Molecular testing in pancreatic cancer. J Clin Oncol. 2023;41(10):1005-1015. doi:10.1200/JCO.22.01989
  17. FDA grants accelerated approval to pemigatinib for cholangiocarcinoma with an FGFR2 rearrangement or fusion. FDA. April 20, 2024. Accessed July 9, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pemigatinib-cholangiocarcinoma-fgfr2-rearrangement-or-fusion/
  18. Rodón J, Damian S, Furqan M, et al. Pemigatinib in previously treated solid tumors with activating FGFR1-FGFR3 alterations: phase 2 FIGHT-207 basket trial. Nat Med. 2024;30(6):1645-1654. doi:10.1038/s41591-024-02934-7
  19. Patel TH, Marcus L, Horiba MN, et al. FDA approval summary: pemigatinib for previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with FGFR2 fusion or other rearrangement. Clin Cancer Res. 2023;29(5):838-842. doi:10.1158/1078-0432.CCR-22-2036
  20. FDA approves erdafitinib for locally advanced or metastatic urothelial carcinoma. FDA. January 19, 2024. Accessed July 9, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-erdafitinib-locally-advanced-or-metastatic-urothelial-carcinoma
  21. Ng CF, Glaspy J, Placencio-Hickok VR, et al. Exceptional response to erdafitinib in FGFR2-mutated metastatic pancreatic ductal adenocarcinoma. J NatlCompr Canc Netw. 2022;20(10):1076-1079. doi:10.6004/jnccn.2022.7039