Tumour heterogeneity and resistance to cancer therapies

Key Points

  • Genomic instability fosters genetic diversity by providing the raw material for the generation of tumour heterogeneity

  • Tumours with high levels of intratumoural heterogeneity might predispose patients to inferior clinical outcomes

  • Under therapeutic selective pressure, resistance to treatment can emerge as a result of the expansion of pre-existing subclonal populations or from the evolution of drug-tolerant cells

  • Serial characterization of genetic variants in plasma samples has the potential to provide information on spatial and temporal heterogeneity on a scale that cannot easily be achieved through analyses of tumour biopsy samples alone

  • Multiregion sampling, research autopsies, and single-cell sequencing are all emerging informative platforms that have the potential to enable decoding of complex clonal relationships at a high level of resolution

  • Combinatorial approaches that pair therapies targeting the predominant, drug-sensitive population of clones in addition to the various subsets of drug-resistant and drug-tolerant cells seem likely to induce the most-durable responses

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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Figure 1: A conceptual framework for distinguishing between spatial and temporal intratumoural heterogeneity.
Figure 2: Distinguishing between linear and branched tumour evolution.
Figure 3: Resistance arises from two distinct evolutionary pathways.
Figure 4: Application of longitudinal plasma profiling.
Figure 5: Correlation between pretreatment tumour heterogeneity and response to targeted 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).

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

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Correspondence to Alice T. Shaw.

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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.

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Dagogo-Jack, I., Shaw, A. Tumour heterogeneity and resistance to cancer therapies. Nat Rev Clin Oncol 15, 81–94 (2018). https://doi.org/10.1038/nrclinonc.2017.166

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