Emergence of Drug Tolerance in Cancer Cell Populations: An Evolutionary Outcome of Selection, Nongenetic Instability, and Stress-Induced Adaptation

Abstract

In recent experiments on isogenetic cancer cell lines, it was observed that exposure to high doses of anticancer drugs can induce the emergence of a subpopulation of weakly proliferative and drug-tolerant cells, which display markers associated with stem cell-like cancer 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-differential equation model of reversible phenotypic evolution in a cell population exposed to cytotoxic drugs. The outcomes of both models suggest that nongenetic instability, stress-induced adaptation, selection, 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 phenotypic fluctuations and selection pressure. These mechanisms can also reverse epigenetic drug tolerance following drug washout. Our study highlights how the transient appearance of the weakly proliferative and drugtolerant 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. Cancer Res; 75(6); 930-9. Ó2015 AACR.

Emergence of cytotoxic resistance in cancer cell populations: Single-cell mechanisms and population-level consequences

“…In [6], we showed that these models are capable of reproducing the main experimental observations detailed in [1]. Our analysis highlighted the important role of non-genetic fluctuations in phenotype in the emergence of drug tolerance in PC9 cancer cell lines.…”

“…However, if appropriate future experimental evidence emerges for this system, such as time series data for proliferation rates or cell density, then this could be used to determine whether an additional mechanism, like stress-induced adaptation of the survival potential, should be added to the basic framework established in [6].…”

Evolutionary dynamics of phenotype-structured populations: from individual-level mechanisms to population-level consequences

“…At this stage, our model does not contain spatial structure, although it could be extended to include spatially distributed phenotypic attributes and migration of individuals at the cost of significantly increased complexity. Despite this simplification, analogous models have already been proven to be capable of shedding some light on the mechanisms which underlie patterns of evolution and adaptation in asexual populations [14][15][16][17][18][19]. From the mathematical point of view, our work follows earlier papers on the derivation of deterministic mesoscopic models from stochastic agent-based models [20][21][22][23][24][25] and the analysis of integrodifferential equations that arise in models of evolutionary dynamics within phenotype-structured populations [26][27][28][29][30][31][32][33].…”

Emergence of cytotoxic resistance in cancer cell populations*

“…In order to address these questions, in [6] we proposed an Individual-Based (I-B) computational model [4,[7][8][9] and an Integro-Differential Equation (IDE) model [10][11][12] of the phenotype evolution observed in [1]. Such models can be used as in silico laboratories to test verbal hypotheses, and uncover mechanisms that underlie emergent features of cancer cell populations.…”