Evolutionary triage governs fitness in driver and passenger mutations and suggests targeting never mutations View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2014-12

AUTHORS

R. A. Gatenby, J. J. Cunningham, J. S. Brown

ABSTRACT

Genetic and epigenetic changes in cancer cells are typically divided into 'drivers' and 'passengers'. Drug development strategies target driver mutations, but inter- and intratumoral heterogeneity usually results in emergence of resistance. Here we model intratumoral evolution in the context of a fecundity/survivorship trade-off. Simulations demonstrate that the fitness value of any genetic change is not fixed but dependent on evolutionary triage governed by initial cell properties, current selection forces and prior genotypic/phenotypic trajectories. We demonstrate that spatial variations in molecular properties of tumour cells are the result of changes in environmental selection forces such as blood flow. Simulated therapies targeting fitness-increasing (driver) mutations usually decrease the tumour burden but almost inevitably fail due to population heterogeneity. An alternative strategy targets gene mutations that are never observed. Because up or downregulation of these genes unconditionally reduces cellular fitness, they are eliminated by evolutionary triage but can be exploited for targeted therapy. More... »

PAGES

5499

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/ncomms6499

DOI

http://dx.doi.org/10.1038/ncomms6499

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1000569751

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/25407411


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