Review Article | Published:

Fibroblast growth factor receptors as treatment targets in clinical oncology

Nature Reviews Clinical Oncology (2018) | Download Citation

Abstract

FGFRs are receptor tyrosine kinases with a role in several biological processes, such as the regulation of development and tissue repair. However, alterations in FGFRs 1–4, such as amplifications, fusions and mutations, as well as aberrant epigenetic or transcriptional regulation and changes in tumour–stromal interactions in the tumour microenvironment, can lead to the development and/or progression of cancer. Similar to other kinase alterations, such alterations are targetable using small molecules or antibodies, and the benefits of FGFR inhibitors have been demonstrated in clinical trials involving subsets of patients with solid tumours harbouring FGFR alterations. However, the response rates in patients with FGFR alterations were relatively low, and responses in patients without detectable FGFR alterations were also observed. In this Review, the author describes the clinical experience with FGFR inhibitors to date, and highlights key aspects that might lead to improved response rates and/or the avoidance of acquired resistance, including the selection of patients who are most likely to benefit from treatment, and the use of FGFR inhibitors in combination regimens with other agents.

Key points

  • FGFR1-amplified oestrogen receptor-positive breast cancer and lung squamous cell carcinoma, FGFR2-amplified gastric cancer, FGFR2-fusion-positive intrahepatic cholangiocarcinoma, FGFR2-mutant endometrial uterine cancer and FGFR3-mutant urothelial carcinoma can all be treated using FGFR inhibitors.

  • Small-molecule inhibitors are the main therapeutic modality used to target FGFR signalling; these agents are classified as either FGFR1/2/3 inhibitors, FGFR4 inhibitors, pan-FGFR inhibitors and multikinase FGFR inhibitors.

  • Antibody-based agents, FGF traps and RNA/DNA aptamers are also under investigation as FGFR-targeted therapeutics.

  • Clinical trials have demonstrated the benefits of FGFR inhibitors in subsets of patients, but also low response rates and the emergence of acquired resistance owing to activation of bypass signalling, gatekeeper mutations and intratumour heterogeneity.

  • Positive and negative selection of patients with tumours harbouring FGFR alterations, the exploration of unknown mechanisms of FGFR overexpression in the absence of FGFR alterations and refined combination strategies are all necessary for the successful clinical application of FGFR inhibitors.

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Acknowledgements

This work was supported in part by a grant-in-aid from M. Katoh’s Fund for the Knowledge-Base Project.

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  1. Department of Omics Network, National Cancer Center, 5-1-1 Tsukiji, Chuo ward, Tokyo, Japan

    • Masaru Katoh

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https://doi.org/10.1038/s41571-018-0115-y