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Spatial competition constrains resistance to targeted cancer therapy

Author

Listed:
  • Katarina Bacevic

    (IGMM, CNRS, University of Montpellier)

  • Robert Noble

    (ISEM, University of Montpellier
    ETH Zürich)

  • Ahmed Soffar

    (IGMM, CNRS, University of Montpellier
    Department of Zoology, Faculty of Science Alexandria University)

  • Orchid Wael Ammar

    (IGMM, CNRS, University of Montpellier)

  • Benjamin Boszonyik

    (IGMM, CNRS, University of Montpellier)

  • Susana Prieto

    (IGMM, CNRS, University of Montpellier)

  • Charles Vincent

    (IRCM, Inserm)

  • Michael E. Hochberg

    (ISEM, University of Montpellier
    Santa Fe Institute)

  • Liliana Krasinska

    (IGMM, CNRS, University of Montpellier)

  • Daniel Fisher

    (IGMM, CNRS, University of Montpellier)

Abstract

Adaptive therapy (AT) aims to control tumour burden by maintaining therapy-sensitive cells to exploit their competition with resistant cells. This relies on the assumption that resistant cells have impaired cellular fitness. Here, using a model of resistance to a pharmacological cyclin-dependent kinase inhibitor (CDKi), we show that this assumption is valid when competition between cells is spatially structured. We generate CDKi-resistant cancer cells and find that they have reduced proliferative fitness and stably rewired cell cycle control pathways. Low-dose CDKi outperforms high-dose CDKi in controlling tumour burden and resistance in tumour spheroids, but not in monolayer culture. Mathematical modelling indicates that tumour spatial structure amplifies the fitness penalty of resistant cells, and identifies their relative fitness as a critical determinant of the clinical benefit of AT. Our results justify further investigation of AT with kinase inhibitors.

Suggested Citation

  • Katarina Bacevic & Robert Noble & Ahmed Soffar & Orchid Wael Ammar & Benjamin Boszonyik & Susana Prieto & Charles Vincent & Michael E. Hochberg & Liliana Krasinska & Daniel Fisher, 2017. "Spatial competition constrains resistance to targeted cancer therapy," Nature Communications, Nature, vol. 8(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01516-1
    DOI: 10.1038/s41467-017-01516-1
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    Cited by:

    1. Elsa Hansen & Jason Karslake & Robert J Woods & Andrew F Read & Kevin B Wood, 2020. "Antibiotics can be used to contain drug-resistant bacteria by maintaining sufficiently large sensitive populations," PLOS Biology, Public Library of Science, vol. 18(5), pages 1-20, May.
    2. Pranav I. Warman & Artem Kaznatcheev & Arturo Araujo & Conor C. Lynch & David Basanta, 2018. "Fractionated Follow-Up Chemotherapy Delays the Onset of Resistance in Bone Metastatic Prostate Cancer," Games, MDPI, vol. 9(2), pages 1-10, April.

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