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Targeting FGFR for the Treatment of Breast Cancer

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

Abstract

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.

Keywords

FGFR breast cancer metastasis kinase inhibition 

Abbreviations

ABC

ATP-binding cassette

BL1

Basal-like 1

BL2

Basal-like 2

BRCA1

Breast cancer 1

CDK

Cyclin-dependent kinase

CSFR1

G-CSF granulocyte-colony stimulating factor

EGFR

Epidermal growth factor receptor

EMT

Epithelial mesenchymal transition

ER-α

Estrogen receptor alpha

ESRP

Epithelial splicing regulatory proteins

FGFR

Fibroblast growth factor receptor

FIIN4

FGFR irreversible inhibitor 4

FLT3

fms-related tyrosine kinase 3

Her2

Human epidermal growth factor receptor 2

Her4

Human epidermal growth factor receptor 4

HSPGs

Hepran sulfate proteogyclans

Ig

Immunoglobulin

IL6

Interleukin 6

IM

Immunomodulatory

INFS

Integrative nuclear FGFR1 signaling

LAR

Luminal androgen receptor

M

Mesenchymal

mAb

Monocloncal antibody

MAP

Mitogen-activated protein

MDSCs

Myeloid derived suppressor cells

MSL

Mesenchymal stem-like

N-cad

N-cadherin

NCAM

Neural cell adhesion molecule

PAM50

Prediction analysis of microarray 50

PARP

Poly ADP-ribose polymerase

PDGFR

Platelet-derived growth factor receptor

PR

Progesterone receptor

Sp1 and 3

Specificity protein 1 and 3

TGF-β

Transforming growth factor-β

TNBC

Triple negative breast cancer

TNFα

Tumor necrosis factor-α

TRE

Thyroid hormone response element

VEGFR

Vascular endothelial growth factor receptor

Notes

Acknowledgments

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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