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Updated: Sep 22, 2025

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Mechanisms of acquired resistance to fibroblast growth factor receptor targeted therapy

David K Lau1,2, Laura Jenkins1,2, Andrew Weickhardt1,2,3

  • 1Olivia Newton John Cancer Research Institute, Heidelberg, Victoria 3084, Australia.

Cancer Drug Resistance (Alhambra, Calif.)
|May 18, 2022
PubMed

Insights

Fibroblast growth factor receptor (FGFR) inhibitors show promise in treating cancers like urothelial carcinoma. This review explores acquired resistance mechanisms to FGFR therapy and strategies to overcome them.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Fibroblast growth factor receptor (FGFR) aberrations drive various cancers, including urothelial carcinoma and cholangiocarcinoma.
  • Targeted oral FGFR inhibitors demonstrate efficacy in preclinical and early clinical trials, leading to tumor size reduction.
  • Larger confirmatory trials are ongoing to validate FGFR inhibitor effectiveness.

Purpose of the Study:

  • To review mechanisms of acquired resistance to fibroblast growth factor receptor (FGFR) inhibitor therapy.
  • To summarize therapeutic strategies aimed at circumventing acquired resistance to FGFR inhibitors.

Main Methods:

  • Literature review of preclinical studies and clinical trials on FGFR inhibitors.
  • Analysis of identified mechanisms of acquired resistance to FGFR targeted therapy.
  • Synthesis of data on strategies to overcome FGFR inhibitor resistance.

Main Results:

  • Acquired resistance to FGFR inhibitors can occur through various mechanisms.
  • These mechanisms include activation of alternative signaling pathways.
  • Tumor clone expansion with specific gatekeeper mutations in the FGFR gene is another resistance pathway.

Conclusions:

  • Understanding acquired resistance mechanisms is crucial for optimizing FGFR inhibitor therapy.
  • Developing strategies to circumvent resistance is essential for durable clinical benefit.
  • Further research is needed to overcome resistance and improve patient outcomes in FGFR-driven malignancies.
Keywords:
Fibroblast growth factor receptoracquired resistancetargeted therapy

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