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  • Review Article
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Fusions in solid tumours: diagnostic strategies, targeted therapy, and acquired resistance

Nature Reviews Clinical Oncology volume 14, pages 735–748 (2017)Cite this article

Subjects

Key Points

  • Oncogenic gene fusions are common in patients with solid tumours and occur across a wide spectrum of tumour types

  • Common methods of fusion detection used in the clinic include break-apart fluorescence in situ hybridization (FISH), immunohistochemistry, and next-generation sequencing

  • Gene fusions frequently involve tyrosine kinases and can cause constitutive kinase activation, augmentation of downstream signalling, and tumour proliferation

  • Targeted therapies are remarkably effective and are approved for patients with fusions involving ALK, ROS1, and PDGFB, and show promise in tumours harbouring fusions in RET, NTRK1/2/3, FGFR1/2/3, and BRAF/CRAF

  • Despite the success of tyrosine-kinase inhibitors (TKIs) in treating tumours with kinase fusions, resistance often develops owing to secondary mutations that disrupt drug binding

  • Treatment with later-generation TKIs can overcome acquired resistance and lead to improved outcomes for patients

Abstract

Structural gene rearrangements resulting in gene fusions are frequent events in solid tumours. The identification of certain activating fusions can aid in the diagnosis and effective treatment of patients with tumours harbouring these alterations. Advances in the techniques used to identify fusions have enabled physicians to detect these alterations in the clinic. Targeted therapies directed at constitutively activated oncogenic tyrosine kinases have proven remarkably effective against cancers with fusions involving ALK, ROS1, or PDGFB, and the efficacy of this approach continues to be explored in malignancies with RET, NTRK1/2/3, FGFR1/2/3, and BRAF/CRAF fusions. Nevertheless, prolonged treatment with such tyrosine-kinase inhibitors (TKIs) leads to the development of acquired resistance to therapy. This resistance can be mediated by mutations that alter drug binding, or by the activation of bypass pathways. Second-generation and third-generation TKIs have been developed to overcome resistance, and have variable levels of activity against tumours harbouring individual mutations that confer resistance to first-generation TKIs. The rational sequential administration of different inhibitors is emerging as a new treatment paradigm for patients with tumours that retain continued dependency on the downstream kinase of interest.

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Figure 1: Discovery of oncogenic fusions.
Figure 2: Structural modelling of putative targeted therapy resistance mutations.
Figure 3: Activity profile of kinase inhibitors targeting specific resistance mutations.
Figure 4: Distribution of kinase fusions across primary tumour sites.

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Acknowledgements

A.M.S. gratefully acknowledges funding support from the National Institutes of Health (award T32-CA009207).

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Authors and Affiliations

  1. Department of Medicine, 1275 York Avenue, New York, 10065, New York, USA

    Alison M. Schram & Alexander Drilon

  2. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, 10065, New York, USA

    Matthew T. Chang & Philip Jonsson

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A.M.S. and A.D. researched data for the article and made a substantial contribution to discussions of content. All authors made a substantial contribution to writing the manuscript and editing and/or reviewing the manuscript before publication.

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Correspondence to Alison M. Schram.

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Competing interests

A.D. has received honoraria from and is an advisory board member for Ariad, AstraZeneca, Blueprint Medicines, Exelixis, Genentech/Roche, Ignyta and Loxo Oncology and has received research funding from Foundation Medicine. The other authors declare no competing interests.

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Supplementary Figure 1

Introduction of agents and novel detection methods for oncogenic fusions in solid tumours. (DOC 138 kb)

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Schram, A., Chang, M., Jonsson, P. et al. Fusions in solid tumours: diagnostic strategies, targeted therapy, and acquired resistance. Nat Rev Clin Oncol 14, 735–748 (2017). https://doi.org/10.1038/nrclinonc.2017.127

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