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Advances and challenges in targeting FGFR signalling in cancer

  • Review Article
  • Published:

From Nature Reviews Cancer

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Key Points

  • Fibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in many developmental and physiological processes through regulation of cell survival and proliferation.

  • Deregulation of FGFR signalling is frequently observed in many types of cancer.

  • Oncogenic FGFR signalling can be deregulated by various mechanisms, such as gene amplification, activating mutations and chromosomal translocations, as well as abnormal FGF ligand-mediated signalling.

  • Downstream FGF signalling frequently activates the MAPK–ERK pathway, and in some contexts the PI3K–AKT and Janus kinase–signal transducer and activator of transcription (JAK–STAT) signalling pathways.

  • Numerous targeted therapies, including small-molecule tyrosine kinase inhibitors (TKIs), FGFR-blocking antibodies and ligand traps, have been developed to attenuate FGFR signalling in cancer, with potent anti-proliferative effects reported in preclinical models.

  • Targeting FGFR in the clinic has had variable results, and identifying cancers that are addicted to the FGFR pathway will be crucial for successful targeting of FGFR in the clinic.

  • Off-target effects of multi-targeting TKIs and the toxicity of selective FGFR inhibitors are limiting factors for effective FGFR targeting. New-generation TKIs and anti-FGFR antibodies offer a promising strategy to overcome the lack of efficacy.

  • Delineating individual contributions of FGFR aberrations to specific cancers would aid better patient stratification and guide more effective treatment strategies to delay the emergence of drug resistance.

Abstract

Fibroblast growth factors (FGFs) and their receptors (FGFRs) regulate numerous cellular processes. Deregulation of FGFR signalling is observed in a subset of many cancers, making activated FGFRs a highly promising potential therapeutic target supported by multiple preclinical studies. However, early-phase clinical trials have produced mixed results with FGFR-targeted cancer therapies, revealing substantial complexity to targeting aberrant FGFR signalling. In this Review, we discuss the increasing understanding of the differences between diverse mechanisms of oncogenic activation of FGFR, and the factors that determine response and resistance to FGFR targeting.

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Figure 1: Mechanisms of oncogenic fibroblast growth factor receptor signalling.
Figure 2: Structure of fibroblast growth factor receptor and frequency of the receptors' somatic mutations with their relative locations.
Figure 3: Mechanisms of resistance to fibroblast growth factor receptor inhibitors.

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Acknowledgements

The authors would like to acknowledge UK National Health Service funding to the UK National Institute for Health Research biomedical research centre at the Royal Marsden Hospital and the Institute of Cancer Research (London, UK). The authors would also like to thank U. Asghar (Institute of Cancer Research) for critical review of the manuscript.

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Authors and Affiliations

  1. Breast Cancer Now Research Centre, Institute of Cancer Research, London, SW3 6JB, UK

    Irina S. Babina & Nicholas C. Turner

  2. Breast Unit, The Royal Marsden Hospital, Fulham Road, London, SW3 6JJ, UK

    Nicholas C. Turner

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  1. Irina S. Babina
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Correspondence to Nicholas C. Turner.

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Competing interests

N.C.T. has received advisory board honoraria from AstraZeneca, Novartis and Servier. I.S.B. declares no competing interests.

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Glossary

Hormone receptor-positive

A type of breast cancer that expresses the oestrogen and progesterone receptors.

Triple-negative breast cancers

A molecular subtype of breast cancer that lacks expression of the oestrogen and progesterone receptors together with human epidermal growth factor receptor 2 (HER2).

Diffuse subtype

A subtype of stomach cancer that is poorly cohesive and infiltrates diffusely; sometimes referred to as 'signet ring cell gastric cancer' because of its characteristic appearance.

Amplicon

A particular sequence or region of DNA or RNA that is susceptible to amplification.

Prohibitin

A family of highly conserved proteins with the characteristic PHB domain that facilitates their predominant localization to mitochondrial and cell membranes, often in lipid rafts.

RECIST partial response

As per the set of rules outlining response evaluation criteria in solid tumours (RECIST), 'partial response' is a decrease in the sum of diameters of target lesions by at least 30%, where the baseline sum of diameters is the reference.

Gene to centromere ratio

A numerical ratio of the copies of a target gene relative to the centromere on chromosome 17, determined by fluorescence in situ hybridization, where values of > 2 suggest target gene amplification.

Hyperphosphataemia

An abnormal elevation of phosphate levels in the blood.

Keratopathy

A condition that is characterized by the appearance of grey bands on the cornea, which are caused by deposits of calcium as a result of increased calcium levels in the blood.

Retinal pigment epithelial detachment

A condition that is characterized by detachment of the retinal pigment epithelium from the connective tissue beneath.

Gatekeeper mutations

Non-synonymous mutations that modulate accessibility of the drug to the ATP-binding domain on a kinase.

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Babina, I., Turner, N. Advances and challenges in targeting FGFR signalling in cancer. Nat Rev Cancer 17, 318–332 (2017). https://doi.org/10.1038/nrc.2017.8

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