Review

Tumour heterogeneity and resistance to cancer therapies

Published online:

Abstract

Cancer is a dynamic disease. During the course of disease, cancers generally become more heterogeneous. As a result of this heterogeneity, the bulk tumour might include a diverse collection of cells harbouring distinct molecular signatures with differential levels of sensitivity to treatment. This heterogeneity might result in a non-uniform distribution of genetically distinct tumour-cell subpopulations across and within disease sites (spatial heterogeneity) or temporal variations in the molecular makeup of cancer cells (temporal heterogeneity). Heterogeneity provides the fuel for resistance; therefore, an accurate assessment of tumour heterogeneity is essential for the development of effective therapies. Multiregion sequencing, single-cell sequencing, analysis of autopsy samples, and longitudinal analysis of liquid biopsy samples are all emerging technologies with considerable potential to dissect the complex clonal architecture of cancers. In this Review, we discuss the driving forces behind intratumoural heterogeneity and the current approaches used to combat this heterogeneity and its consequences. We also explore how clinical assessments of tumour heterogeneity might facilitate the development of more-effective personalized therapies.

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Acknowledgements

I.D.-J. gratefully acknowledges support from the American Society of Clinical Oncology (ASCO). A.T.S. gratefully acknowledges support from LungStrong, the US Department of Health & Human Services, the US National Foundation for Cancer Research, and the US National Institutes of Health (NIH; grant R01CA164273).

Author information

Affiliations

  1. Department of Medicine, Massachusetts General Hospital, 32 Fruit Street, Yawkey 7B, Boston, Massachusetts 02114, USA.

    • Ibiayi Dagogo-Jack
    •  & Alice T. Shaw

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Contributions

Both authors made a substantial contribution to all aspects of the preparation of this manuscript before submission.

Competing interests

I.D.-J. has acted as a consultant of or has received honoraria from Boehringer Ingelheim and Foundation Medicine. A.T.S. has acted as a consultant of or has received honoraria from Ariad/Takeda, Blueprint Medicines, Foundation Medicine, Genentech/Roche, Ignyta, KSQ therapeutics, LOXO, Novartis, and Pfizer.

Corresponding author

Correspondence to Alice T. Shaw.