Targeting FGFR for the Treatment of Breast Cancer

  • Remah Ali
  • Saeed S. Akhand
  • Michael K. WendtEmail author
Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (RTACT, volume 16)


Breast cancer has been detailed at the molecular level in very high definition. These molecular characterizations have allowed for the establishment of at least 5 distinct subtypes of the disease. Importantly, breast cancer subtyping can predict for tumor recurrence and drives the clinical application of endocrine and human epidermal growth factor receptor 2 (Her2)-targeted therapies. Recent studies have revealed that these subtypes of breast cancer are not static definitions and that through disease progression breast cancers have the ability to switch subtypes to acquire resistance to these therapies. In addition to therapeutic failure in the metastatic setting, other patients’ primary tumors can only be defined as the poorly understood basal subtype, a classification that is synonymous with the description of triple negative breast cancer (TNBC). Unfortunately, these patients are not candidates for any currently approved molecular therapies and they are left with suboptimal, highly cytotoxic chemotherapies as treatment options. Therefore, recent research has focused on identifying the molecular drivers of TNBC and metastatic breast cancer that has undergone subtype switching and become resistant to endocrine and Her2-targeted therapies. One emerging target for the treatment of these advanced forms of breast cancer is the fibroblast growth factor receptor (FGFR). FGFR plays critical roles in the metastatic progression of TNBC and the acquisition of resistance to targeted therapies as well as chemotherapy. Herein, we review the current understanding of how FGFR is regulated in breast cancer and what approaches are currently being taken to pharmacologically target FGFR function as a therapeutic option for breast cancer patients. In addition to being amplified at the genomic level, FGFRs are highly inducible genes and their biology is made more complex by factors that include alternative splicing, differential subcellular localization and the presence of several different coreceptors and ligands. Finally, gatekeeper mutations in the receptor and activation of alternative growth factor pathways can give rise to acquired resistance to FGFR inhibitors. Recent clinical trials using FGFR kinase inhibitors emphasize that these biological factors need to be taken into diagnostic consideration when identifying the optimal patient population for FGFR-targeted therapies.


FGFR breast cancer metastasis kinase inhibition 



ATP-binding cassette


Basal-like 1


Basal-like 2


Breast cancer 1


Cyclin-dependent kinase


G-CSF granulocyte-colony stimulating factor


Epidermal growth factor receptor


Epithelial mesenchymal transition


Estrogen receptor alpha


Epithelial splicing regulatory proteins


Fibroblast growth factor receptor


FGFR irreversible inhibitor 4


fms-related tyrosine kinase 3


Human epidermal growth factor receptor 2


Human epidermal growth factor receptor 4


Hepran sulfate proteogyclans




Interleukin 6




Integrative nuclear FGFR1 signaling


Luminal androgen receptor




Monocloncal antibody


Mitogen-activated protein


Myeloid derived suppressor cells


Mesenchymal stem-like




Neural cell adhesion molecule


Prediction analysis of microarray 50


Poly ADP-ribose polymerase


Platelet-derived growth factor receptor


Progesterone receptor

Sp1 and 3

Specificity protein 1 and 3


Transforming growth factor-β


Triple negative breast cancer


Tumor necrosis factor-α


Thyroid hormone response element


Vascular endothelial growth factor receptor



Members of the Wendt Laboratory are thanked for critical reading of the manuscript. This work was supported in part by the National Institutes of Health (R00CA166140), the American Cancer Society (RSG-16-172-01) and the METavivor foundation.

No Conflict Statement

No potential conflicts of interest were disclosed.


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Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Remah Ali
    • 1
  • Saeed S. Akhand
    • 1
  • Michael K. Wendt
    • 1
    Email author
  1. 1.Purdue University Center for Cancer Research, Department of Medicinal Chemistry and Molecular PharmacologyPurdue UniversityWest LafayetteUSA

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