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FGFR-TKI resistance in cancer: current status and perspectives

Sitong Yue1, Yukun Li2, Xiaojuan Chen1

  • 1Department of Oncology, Laboratory of Structural Biology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.

Journal of Hematology & Oncology
|February 11, 2021
PubMed

Insights

Resistance to fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors (TKI) in cancer is a growing concern. This review explores resistance mechanisms and strategies to overcome them, advancing precision cancer medicine.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Fibroblast growth factor receptors (FGFRs) are crucial in cancer cell proliferation, differentiation, and migration.
  • Fibroblast growth factor receptor tyrosine kinase inhibitors (FGFR-TKI) have shown success in targeted cancer therapy.
  • Acquired resistance to FGFR-TKI poses a significant clinical challenge, limiting treatment efficacy.

Purpose of the Study:

  • To review the known mechanisms driving resistance to FGFR-TKI in various cancer types.
  • To summarize emerging strategies for overcoming FGFR-TKI resistance.
  • To provide insights for developing more effective, individualized cancer treatments.

Main Methods:

  • Comprehensive literature review of studies on FGFR-TKI resistance.
  • Analysis of identified resistance mechanisms, including genetic and non-genetic factors.
  • Evaluation of preclinical and clinical data on therapeutic strategies to combat resistance.

Main Results:

  • Key resistance mechanisms identified include gatekeeper mutations, activation of alternative signaling pathways, lysosome-mediated TKI sequestration, and gene fusions.
  • Strategies to overcome resistance encompass developing covalent inhibitors, dual-target inhibitors, combination therapies, and lysosome-targeting agents.
  • Understanding these mechanisms and strategies is vital for improving patient outcomes.

Conclusions:

  • FGFR-TKI resistance is multifactorial, involving genetic alterations and adaptive signaling.
  • Novel therapeutic approaches are being developed to circumvent or overcome resistance.
  • These advancements pave the way for more personalized and effective precision medicine strategies in oncology.
Keywords:
Drug resistanceFGFRGatekeeper mutationLysosome sequestrationTyrosine kinase inhibitor

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