Exploiting evolutionary steering to induce collateral drug sensitivity in cancer

Ahmet Acar, Daniel Nichol, Javier Fernandez-Mateos, George D. Cresswell, Iros Barozzi, Sung Pil Hong, Nicholas Trahearn, Inmaculada Spiteri, Mark Stubbs, Rosemary Burke, Adam Stewart, Giulio Caravagna, Benjamin Werner, Georgios Vlachogiannis, Carlo C. Maley, Luca Magnani, Nicola Valeri, Udai Banerji, Andrea Sottoriva

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1 Scopus citations

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.

Original languageEnglish (US)
Article number1923
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Acar, A., Nichol, D., Fernandez-Mateos, J., Cresswell, G. D., Barozzi, I., Hong, S. P., Trahearn, N., Spiteri, I., Stubbs, M., Burke, R., Stewart, A., Caravagna, G., Werner, B., Vlachogiannis, G., Maley, C. C., Magnani, L., Valeri, N., Banerji, U., & Sottoriva, A. (2020). Exploiting evolutionary steering to induce collateral drug sensitivity in cancer. Nature communications, 11(1), [1923]. https://doi.org/10.1038/s41467-020-15596-z