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| Epigenetic mechanisms are becoming increasingly implicated in the evolution of drug-resistance in cancer cell populations. However, these mechanisms are not well understood. Recent experiments on NSCLC-derived (PC9) cell lines revealed a sub-population of cells that, in response to anti-cancer drugs, were able to acquire transient drug-resistance (Sharma et al., Cell, 2010). Interestingly, this reversible drug-tolerant state was shown to be the result of epigenetic modifications, rather than genetic mutation.
Motivated by these results, we formulate a mathematical model of phenotype variation in a cancer cell population in order to understand the mechanisms responsible for the reversible, drug-resistant phenotype observed in NSCLC-derived (PC9) cell lines. We assume that both stochastic variation in cell phenotype due to biological noise and stress-induced adaption are functioning in parallel without genetic mutation. Our model recovers the evolution of the PC9 cells into the drug-tolerant cells in the presence of a cytotoxic drug therapy. It also captures the dynamics of drug-resensitisation that were observed after drug-washout. |
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