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

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 tr...

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Bibliographic Details
Published in:EMBO molecular medicine 2012-08, Vol.4 (8), p.675-684
Main Authors: Saunders, Nicholas A., Simpson, Fiona, Thompson, Erik W., Hill, Michelle M., Endo‐Munoz, Liliana, Leggatt, Graham, Minchin, Rodney F., Guminski, Alexander
Format: Article
Language:English
Subjects:
Antineoplastic Agents - pharmacology
Biology
Cancer
Cancer therapies
Chemotherapy
clonal variants
Cytotoxicity
Deoxyribonucleic acid
DNA
DNA repair
Drug resistance
Drug Resistance, Neoplasm
Enzymes
Epigenetics
Gene amplification
Genetic diversity
Genetic Variation
Humans
intratumoural heterogeneity
Kinases
Metabolism
Mortality
Mutation
Neoplasms - drug therapy
Patients
Plasticity
Review
Stochasticity
Tumors
tumour cell plasticity
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Summary: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.
ISSN:1757-4676
1757-4684
DOI:10.1002/emmm.201101131