Role of intratumoural heterogeneity in cancer drug resistance: molecular and clinical perspectives

Authors

  • Nicholas A. Saunders,

    Corresponding author
    1. Epithelial Cancer Program, University of Queensland, Diamantine Institute, Princess Alexandra Hospital, Queensland, Australia
    2. Epithelial Pathobiology Group, Princess Alexandra Hospital, University of Queensland, Diamantina Institute, Woolloongabba, Queensland, Australia
    3. School of Biomedical Sciences, University of Queensland, Woolloongabba, Queensland, Australia
    • Tel: +61732405894; Fax: +61732405946

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  • Fiona Simpson,

    1. Epithelial Cancer Program, University of Queensland, Diamantine Institute, Princess Alexandra Hospital, Queensland, Australia
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  • Erik W. Thompson,

    1. Department of Surgery, University of Melbourne, St. Vincent's Hospital, Melbourne, Victoria, Australia
    2. St. Vincent's Institute, Melbourne, Victoria, Australia
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  • Michelle M. Hill,

    1. Epithelial Cancer Program, University of Queensland, Diamantine Institute, Princess Alexandra Hospital, Queensland, Australia
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  • Liliana Endo-Munoz,

    1. Epithelial Cancer Program, University of Queensland, Diamantine Institute, Princess Alexandra Hospital, Queensland, Australia
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  • Graham Leggatt,

    1. Epithelial Cancer Program, University of Queensland, Diamantine Institute, Princess Alexandra Hospital, Queensland, Australia
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  • Rodney F. Minchin,

    1. School of Biomedical Sciences, University of Queensland, Woolloongabba, Queensland, Australia
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  • Alexander Guminski

    1. Department of Medical Oncology, Royal North Shore Hospital, Sydney, New South Wales, Australia
    2. Department of Medicine, University of Sydney, Sydney, New South Wales, Australia
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Abstract

Drug resistance continues to be a major barrier to the delivery of curative therapies in cancer. Historically, drug resistance has been associated with over-expression of drug transporters, changes in drug kinetics or amplification of drug targets. However, the emergence of resistance in patients treated with new-targeted therapies has provided new insight into the complexities underlying cancer drug resistance. Recent data now implicate intratumoural heterogeneity as a major driver of drug resistance. Single cell sequencing studies that identified multiple genetically distinct variants within human tumours clearly demonstrate the heterogeneous nature of human tumours. The major contributors to intratumoural heterogeneity are (i) genetic variation, (ii) stochastic processes, (iii) the microenvironment and (iv) cell and tissue plasticity. Each of these factors impacts on drug sensitivity. To deliver curative therapies to patients, modification of current therapeutic strategies to include methods that estimate intratumoural heterogeneity and plasticity will be essential.

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