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Directly targeting transcriptional dysregulation in cancer

Nature Reviews Cancer volume 15, pages 686–694 (2015)Cite this article

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Abstract

Drugs that target intracellular signalling pathways have markedly improved progression-free survival of patients with cancers who were previously regarded as untreatable. However, the rapid emergence of therapeutic resistance, as a result of bypass signalling or downstream mutation within kinase-mediated signalling cascades, has curtailed the benefit gained from these therapies. Such resistance mechanisms are facilitated by the linearity and redundancy of kinase signalling pathways. We argue that, in each cancer, the dysregulation of key transcriptional regulators not only defines the cancer phenotype but is essential for its development and maintenance. Furthermore, we propose that, as therapeutic targets, these transcriptional regulators are less prone to bypass by alternative mutational events or clonal heterogeneity, and therefore we must rekindle our efforts to directly target transcriptional regulation across a broad range of cancers.

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Figure 1: The architecture of oncogenic signalling pathways provides multiple opportunities for bypass-mediated therapeutic resistance.
Figure 2: The balance between proliferation and differentiation is directly dependent on transcription.
Figure 3: Transcriptional regulators such as MYB induce the expression of multiple pro-oncogenic drivers.
Figure 4: Complexity of transcription factor networks.
Figure 5: Modes of targeting transcriptional regulators.

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Acknowledgements

Relevant work in the authors' laboratories has been supported in part by grants from the National Health and Medical Research Council, Australia; Cancer Council Queensland, Australia; The World Cancer Research Fund International (formerly known as AICR), UK; and the Leukaemia Foundation of Australia. The authors also thank F. Simpson and M. Dawson for valuable comments on the manuscript, and apologize to the many authors whose work they could not cite owing to space limitations.

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  1. School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence (PACE), 20 Cornwall Street, Woolloongabba, 4102, Queensland, Australia

    Thomas J. Gonda

  2. Peter MacCallum Cancer Centre and the Sir Peter MacCallum Oncology Department and the Pathology Department, University of Melbourne, Parkville, 3010, Victoria, Australia

    Robert G. Ramsay

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Correspondence to Thomas J. Gonda.

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Gonda, T., Ramsay, R. Directly targeting transcriptional dysregulation in cancer. Nat Rev Cancer 15, 686–694 (2015). https://doi.org/10.1038/nrc4018

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