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  • Review Article
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Tyrosine kinase gene rearrangements in epithelial malignancies

Nature Reviews Cancer volume 13, pages 772–787 (2013)Cite this article

Subjects

Key Points

  • Chromosomal rearrangements that lead to oncogenic kinase activation are an emerging paradigm in epithelial cancers.

  • Ten different tyrosine kinases have currently been identified as fusion kinases in various different epithelial tumours. Tyrosine kinase gene rearrangements generally define molecularly distinct subsets of patients.

  • Cancers that harbour tyrosine kinase gene rearrangements express activated fusion kinases that drive the initiation and progression of malignancy. These cancers become dependent on (or 'addicted' to) continued signalling from the oncogenic fusion kinase.

  • Several tyrosine kinase inhibitors have been shown to be active in cancers that harbour specific tyrosine kinase fusions, which validates these fusion kinases as bona fide targets. In the case of anaplastic lymphoma kinase (ALK)-rearranged lung cancers, ALK inhibitors like crizotinib have become a standard therapy.

  • Multiplexed genetic analyses that include screening for tyrosine kinase fusions will help to accelerate the process of target discovery and clinical validation.

Abstract

Chromosomal rearrangements that lead to oncogenic kinase activation are observed in many epithelial cancers. These cancers express activated fusion kinases that drive the initiation and progression of malignancy, and often have a considerable response to small-molecule kinase inhibitors, which validates these fusion kinases as 'druggable' targets. In this Review, we examine the aetiologic, pathogenic and clinical features that are associated with cancers harbouring oncogenic fusion kinases, including anaplastic lymphoma kinase (ALK), ROS1 and RET. We discuss the clinical outcomes with targeted therapies and explore strategies to discover additional kinases that are activated by chromosomal rearrangements in solid tumours.

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Figure 1: Molecular aetiology and types of chromosomal rearrangements.
Figure 2: Genomic organization of tyrosine kinase rearrangements.

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Acknowledgements

The authors are supported by grants from the US National Institutes of Health (NIH) 5R01CA164273-02 (A.T.S. and J.A.E.), V Foundation for Cancer Research (A.T.S. and J.A.E.), and Uniting Against Lung Cancer (A.T.S.). A.T.S. is the Charles W. and Jennifer C. Johnson Koch Institute Clinical Investigator. The authors thank I. Klein for his helpful comments, and Be a Piece of the Solution and the Evan Spirito Memorial Foundation for support of lung cancer research.

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  1. Massachusetts General Hospital Cancer Center, Boston, 02114, Massachusetts, USA

    Alice T. Shaw, Peggy P. Hsu, Mark M. Awad & Jeffrey A. Engelman

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A.T.S. is a consultant for Pfizer, Novartis, Ariad, Chugai, Daiichi-sankyo, Genentech. J.A.E is a consultant for Agios, AstraZeneca, Cell Signaling Technology, Chugai, GlaxoSmithKline, Novartis and Sanofi Aventis; research funding from Novartis, Sanofi Aventis, AstraZeneca, GlaxoSmithKline; equity in Agios and Gatekeeper.

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Shaw, A., Hsu, P., Awad, M. et al. Tyrosine kinase gene rearrangements in epithelial malignancies. Nat Rev Cancer 13, 772–787 (2013). https://doi.org/10.1038/nrc3612

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