TY - JOUR
T1 - Exploiting evolutionary steering to induce collateral drug sensitivity in cancer
AU - Acar, Ahmet
AU - Nichol, Daniel
AU - Fernandez-Mateos, Javier
AU - Cresswell, George D.
AU - Barozzi, Iros
AU - Hong, Sung Pil
AU - Trahearn, Nicholas
AU - Spiteri, Inmaculada
AU - Stubbs, Mark
AU - Burke, Rosemary
AU - Stewart, Adam
AU - Caravagna, Giulio
AU - Werner, Benjamin
AU - Vlachogiannis, Georgios
AU - Maley, Carlo C.
AU - Magnani, Luca
AU - Valeri, Nicola
AU - Banerji, Udai
AU - Sottoriva, Andrea
N1 - Funding Information:
A.S. is supported by the Wellcome Trust (202778/B/16/Z) and Cancer Research UK (A22909). We acknowledge funding from the National Institute of Health (NCI U54 CA217376) to A.S. and C.C.M. This work was also supported by Wellcome Trust award to the Centre for Evolution and Cancer (105104/Z/14/Z). U.B. is supported by The NIHR (RP-2016-07-28), CRUK (A25128, A22897) and by the Experimental Cancer Medicine Centre grant and the NIHR Biomedical Research Centre grant to The Institute of Cancer Research and The Royal Marsden NHS Foundation trust. C.C.M. was supported in part by NIH grants U54 CA217376, P01 CA91955, R01 CA170595, R01 CA185138 and R01 CA140657 as well as CDMRP Breast Cancer Research Programme Award BC132057 and an Arizona Investigator Grant ADHS18-198847. L.M. was supported by Cancer Research UK (A23110). NV is supported by Cancer Research UK (A18052 and A26815), the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research (grant numbers A62, A100, A101, A159) and the European Union FP7 (CIG 334261). We thank Nik Matthews and the Tumour Profiling Unit at the ICR for their support with Next-Generation Sequencing. We also thank Michael Hubank, Eleni Koutroumanidou and Debbie Hughes for technical support.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-15596-z
DO - 10.1038/s41467-020-15596-z
M3 - Article
C2 - 32317663
AN - SCOPUS:85083774989
VL - 11
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1923
ER -
