Exploiting evolutionary steering to induce collateral drug sensitivity in cancer
File(s)2020_acar_et_al.pdf (8.83 MB)
Published version
Author(s)
Type
Journal Article
Abstract
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.
Date Issued
2020-04-21
Online Publication Date
2020-07-31T15:33:59Z
Date Acceptance
2020-03-18
ISSN
2041-1723
Publisher
Nature Research
Start Page
1
End Page
14
Journal / Book Title
Nature Communications
Volume
11
Issue
1
Copyright Statement
© The Author(s) 2020. This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative
Commons license, and indicate if changes were made. The images or other third party
material in this article are included in the article’s Creative Commons license, unless
indicated otherwise in a credit line to the material. If material is not included in the
article’s Creative Commons license and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from
the copyright holder. To view a copy of this license, visit http://creativecommons.org/
licenses/by/4.0/.
Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative
Commons license, and indicate if changes were made. The images or other third party
material in this article are included in the article’s Creative Commons license, unless
indicated otherwise in a credit line to the material. If material is not included in the
article’s Creative Commons license and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from
the copyright holder. To view a copy of this license, visit http://creativecommons.org/
licenses/by/4.0/.
License URI
Identifier
https://www.nature.com/articles/s41467-020-15596-z
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000529513400001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
CELL LUNG-CANCER
CLONAL EVOLUTION
TARGETED THERAPY
TUMOR HETEROGENEITY
ACQUIRED-RESISTANCE
EGFR BLOCKADE
COPY NUMBER
COMPETITION
INHIBITORS
MUTATIONS
Antineoplastic Agents
Clonal Evolution
Computational Biology
Computer Simulation
Drug Resistance, Neoplasm
Evolution, Molecular
Gefitinib
Genotype
Humans
Lung Neoplasms
Models, Theoretical
Molecular Medicine
Pyridones
Pyrimidinones
Stochastic Processes
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
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
CELL LUNG-CANCER
CLONAL EVOLUTION
TARGETED THERAPY
TUMOR HETEROGENEITY
ACQUIRED-RESISTANCE
EGFR BLOCKADE
COPY NUMBER
COMPETITION
INHIBITORS
MUTATIONS
Publication Status
Published
Article Number
ARTN 1923
Date Publish Online
2020-04-21