FGFR4: A promising therapeutic target for breast cancer and other solid tumors

Pharmacol Ther. 2020 Oct;214:107590. doi: 10.1016/j.pharmthera.2020.107590. Epub 2020 May 31.

Abstract

The fibroblast growth factor receptor (FGFR) signaling pathway has long been known to cancer researchers because of its role in cell survival, proliferation, migration, and angiogenesis. Dysregulation of FGFR signaling is frequently reported in cancer studies, but most of these studies focus on FGFR1-3. However, there is growing evidence implicating an important and unique role of FGFR4 in oncogenesis, tumor progression, and resistance to anti-tumor therapy in multiple types of cancer. Importantly, there are several novel FGFR4-specific inhibitors in clinical trials, making FGFR4 an attractive target for further research. In this review, we focus on assessing the role of FGFR4 in cancer, with an emphasis on breast cancer. First, the structure, physiological functions and downstream signaling pathways of FGFR4 are introduced. Next, different mechanisms reported to cause aberrant FGFR4 activation and their functions in cancer are discussed, including FGFR4 overexpression, FGF ligand overexpression, FGFR4 somatic hotspot mutations, and the FGFR4 G388R single nucleotide polymorphism. Finally, ongoing and recently completed clinical trials targeting FGFRs in cancer are reviewed, highlighting the therapeutic potential of FGFR4 inhibition for the treatment of breast cancer.

Keywords: Breast cancer; Cancer; FGFR4; Fibroblast growth factor receptor; Precision medicine; Targeted therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / therapeutic use*
  • Biomarkers, Tumor / antagonists & inhibitors*
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Molecular Targeted Therapy
  • Mutation
  • Polymorphism, Single Nucleotide
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / therapeutic use*
  • Receptor, Fibroblast Growth Factor, Type 4 / antagonists & inhibitors*
  • Receptor, Fibroblast Growth Factor, Type 4 / genetics
  • Receptor, Fibroblast Growth Factor, Type 4 / metabolism
  • Signal Transduction

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Protein Kinase Inhibitors
  • FGFR4 protein, human
  • Receptor, Fibroblast Growth Factor, Type 4