Exploiting evolutionary steering to induce collateral drug sensitivity in cancer.
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Date
2020-04-21ICR Author
Author
Acar, A
Nichol, D
Fernandez-Mateos, J
Cresswell, GD
Barozzi, I
Hong, SP
Trahearn, N
Spiteri, I
Stubbs, M
Burke, R
Stewart, A
Caravagna, G
Werner, B
Vlachogiannis, G
Maley, CC
Magnani, L
Valeri, N
Banerji, U
Sottoriva, A
Type
Journal Article
Metadata
Show full item recordAbstract
Drug resistance mediated by clonal evolution is arguably the biggest problem in cancer therapy today. However, evolving resistance to one drug may come at a cost of decreased fecundity or increased sensitivity to another drug. These evolutionary trade-offs can be exploited using 'evolutionary steering' to control the tumour population and delay resistance. However, recapitulating cancer evolutionary dynamics experimentally remains challenging. Here, we present an approach for evolutionary steering based on a combination of single-cell barcoding, large populations of 108-109 cells grown without re-plating, longitudinal non-destructive monitoring of cancer clones, and mathematical modelling of tumour evolution. We demonstrate evolutionary steering in a lung cancer model, showing that it shifts the clonal composition of the tumour in our favour, leading to collateral sensitivity and proliferative costs. Genomic profiling revealed some of the mechanisms that drive evolved sensitivity. This approach allows modelling evolutionary steering strategies that can potentially control treatment resistance.
Subject
Humans
Lung Neoplasms
Pyridones
Pyrimidinones
Antineoplastic Agents
Stochastic Processes
Computational Biology
Evolution, Molecular
Drug Resistance, Neoplasm
Genotype
Models, Theoretical
Computer Simulation
Clonal Evolution
Molecular Medicine
Gefitinib
Research team
Clinical Pharmacology – Adaptive Therapy
Evolutionary Genomics & Modelling
Gastrointestinal Cancer Biology and Genomics
Hit Discovery & Structural Design
Language
eng
Date accepted
2020-03-18
License start date
2020-04-21
Citation
Nature communications, 2020, 11 (1), pp. 1923 - ?
Publisher
NATURE PORTFOLIO