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Emergence of drug tolerance in cancer cell populations: an evolutionary outcome of selection, non-genetic instability and stress-induced adaptation

Abstract : In recent experiments on isogenetic cancer cell lines, it was observed that exposure to high doses of anti-cancer drugs can induce the emergence of a subpopulation of weakly-proliferative and drug-tolerant cells, that display markers associated with cancer stem cells. After a period of time, some of the surviving cells were observed to change their phenotype to resume normal proliferation, and eventually repopulate the sample. Furthermore, the drug-tolerant cells could be drug resensitized following drug washout. Here we propose a theoretical mechanism for the transient emergence of such drug tolerance. In this framework, we formulate an individual-based model and an integro-di fferential equation model of reversible phenotypic evolution in a cell population exposed to cytotoxic drugs. The outcomes of both models suggest that selection, non-genetic instability, stress-induced adaptation and the interplay between these mechanisms can push an actively proliferating cell population to transition into a weakly-proliferative and drug-tolerant state. Hence, the cell population experiences much less stress in the presence of the drugs and, in the long run, reacquires a proliferative phenotype, due to selection pressure and phenotypic fluctuations. These mechanisms can also reverse epigenetic drug-tolerance following drug washout. Our study highlights how the transient appearance of the weakly-proliferative and drug-tolerant cells is related to the use of high-dose therapy. Furthermore, we show how stem-like characteristics can act to stabilize the transient, weakly-proliferative and drug-tolerant subpopulation for a longer time window. Finally, using our models as in silico laboratories, we propose new testable hypotheses that could help uncover general principles underlying the emergence of cancer drug tolerance.
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https://hal.archives-ouvertes.fr/hal-01111271
Contributor : Tommaso Lorenzi Connect in order to contact the contributor
Submitted on : Friday, January 30, 2015 - 7:58:03 AM
Last modification on : Friday, January 21, 2022 - 3:19:11 AM
Long-term archiving on: : Saturday, April 15, 2017 - 11:47:09 PM

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  • HAL Id : hal-01111271, version 1

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Rebecca H. Chisholm, Tommaso Lorenzi, Alexander Lorz, Annette K. Larsen, Luís Almeida, et al.. Emergence of drug tolerance in cancer cell populations: an evolutionary outcome of selection, non-genetic instability and stress-induced adaptation. 2015. ⟨hal-01111271⟩

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