Drug resistance: origins, evolution and characterization of genomic clones and the tumor ecosystem to optimize precise individualized therapy

•The mechanisms underlying cancer drug resistance remain poorly understood.•Genomic clones or interaction networks drive therapeutic resistance.•Genetic, genomic and transcriptional heterogeneity dictate individualized precise therapy.•A clinico-genomic network model could speed up the advent of pre...

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Bibliographic Details
Published in:Drug discovery today 2019-06, Vol.24 (6), p.1281-1294
Main Authors: Kyrochristos, Ioannis D., Ziogas, Demosthenes E., Roukos, Dimitrios H.
Format: Article
Language:English
Subjects:
Animals
Drug Resistance, Neoplasm - genetics
Ecosystem
Genomics - methods
Humans
Neoplasms - genetics
Precision Medicine - methods
Transcriptome - genetics
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Summary:•The mechanisms underlying cancer drug resistance remain poorly understood.•Genomic clones or interaction networks drive therapeutic resistance.•Genetic, genomic and transcriptional heterogeneity dictate individualized precise therapy.•A clinico-genomic network model could speed up the advent of precision oncology. Progress in understanding and overcoming fatal intrinsic and acquired resistance is slow, with only a few exceptions. Despite advances in modern genome and transcriptome analysis, the controversy of the three different theories on drug resistance and tumor progression, namely dynamic intratumor heterogeneity, pre-existing minor genomic clones and tumor ecosystem, is unresolved. Moreover, evidence on transcriptional heterogeneity suggests the necessity of a drug bank for individualized, precise drug-sensitivity prediction. We propose a cancer type- and stage-specific clinicogenomic and tumor ecosystemic concept toward cancer precision medicine, focusing on early therapeutic resistance and relapse.
ISSN:1359-6446
1878-5832
DOI:10.1016/j.drudis.2019.04.008