The Role of Cell Density and Intratumoral Heterogeneity in Multidrug Resistance

Lavi, Orit; Greene, James M.; Levy, Doron; Gottesman, Michael M.

doi:10.1158/0008-5472.can-13-1768

Cited by 66 publications

(69 citation statements)

References 23 publications

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“…On the other hand, robust cells, with a high survival potential, experience much less stress in the presence of the drugs and will not be induced to lower their proliferation rate. Motivated by these considerations, here, we propose an individual-based (I-B) computational model (11,(26)(27)(28) and an integro-differential equation (IDE) model (29)(30)(31) of the phenotype evolution observed in ref. 12.…”

Section: Extended Individual-based Modelmentioning

confidence: 99%

“…Unlike previous models of resistance in cancer cell populations that focus on the evolution of just one phenotypic trait (11,(27)(28)(29)(30)(31), here, we introduce a novel strategy to model the effects of stress-induced adaptation, and we focus on the evolution of two phenotypic traits that show substantial variability during drug treatment and after drug washout: a cell's survival potential and proliferation potential. Throughout, we consider the proliferation potential and survival potential of cells separately.…”

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confidence: 99%

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

et al. 2015

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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.

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Section: Extended Individual-based Modelmentioning

confidence: 99%

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confidence: 99%

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

et al. 2015

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“…As examples, pre-existing BCR-ABL kinase domain mutations confer resistance to the tyrosine kinase inhibitor imatinib in chronic myeloid leukemia patients [66,36], and pre-existing MEK1 mutations confer resistance to BRAF inhibitors in melanoma patients [8]. Many mathematical models have considered how the presence of preexisting resistant cells impact cancer progression and treatment [37,39,58,40,23,24,70,16,60,63,4,22,44,3,32,80,29,49,57,59,77,68,9,10].On the other hand, acquired drug resistance broadly describes the case in which drug resistance develops during the course of therapy from a population of cells that were initially drug sensitive [34]. The term "acquired resistance" is really an umbrella term for two distinct phenomena, which complicates the study of acquired resistance.…”

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confidence: 99%

“…Mathematical modeling studies in particular have been used to explore both broad and detailed aspects of cancer drug resistance, as reviewed in [43,7,25]. The fundamental question of how the presence of drug resistant cells influences tumor dynamics and treatment outcomes has been thoroughly explored in mathematical models under a wide variety of assumptions [14,37,39,47,58,40,23,24,70,16,45,60,63,4,22,33,44,52,65,3,32,80,13,26,29,46,49,51,57,59,77,18,68,1,9,10,20]. Cancer models have also been utilized to assess how various underlying mechanisms contribute to the resistant phenotype [80,13,59,18,20], and to calculate the probability that drug resistance emerges within a specified time frame, be it before or during cancer treatment …”

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confidence: 99%

A mathematical approach to differentiate spontaneous and induced evolution to drug resistance during cancer treatment

Greene

Gevertz

Sontag

2017

Preprint

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Resistance to chemotherapy is a major impediment to the successful treatment of cancer. Classically, resistance has been thought to arise primarily through random genetic mutations, after which mutated cells expand via Darwinian selection. However, recent experimental evidence suggests that the progression to drug resistance need not occur randomly, but instead may be induced by the therapeutic agent itself. This process of resistance induction can be a result of genetic changes, or can occur through epigenetic alterations that cause otherwise drug-sensitive cancer cells to undergo phenotype switching. This relatively novel notion of resistance further complicates the already challenging task of designing treatment protocols that minimize the risk of developing drug resistance. In an effort to better understand resistance to treatment, we have developed a mathematical modeling framework that incorporates both random and drug-induced resistance. Our model demonstrates that the ability (or lack thereof) of a drug to induce resistance can result in qualitatively different responses to the same drug dose and delivery schedule. The importance of induced resistance in treatment response led us to ask if, in our model, one can determine the resistance induction rate of a drug for a given treatment protocol. Not only could we prove that the induction parameter in our model is theoretically identifiable, we have also proposed a possible in vitro protocol which could potentially be used to determine a treatment's propensity to induce resistance. (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/235150 doi: bioRxiv preprint first posted online Dec. 15, 2017; Tumor resistance to chemotherapy and targeted drugs is a major cause of treatment failure. Both molecular and microenvironmental factors have been implicated in the development of drug resistance [34]. As an example of molecular resistance, the upregulation of drug efflux transporters can prevent sufficiently high intracellular drug accumulation, limiting treatment efficacy [31]. Other molecular causes of drug resistance include modification of drug targets, enhanced DNA damage repair mechanisms, dysregulation of apoptotic pathways, and the presence of cancer stem cells [31,17,34,78,81]. The irregular tumor vasculature which results in inconsistent drug distribution and hypoxia is an example of a microenvironmental factor that impacts drug resistance [76]. Other characteristics of the tumor microenvironment that influence drug resistance include regions of acidity, immune cell infiltration and activation, and the tumor stroma [27,76,56,15,34,55].Research continues to shed light on the multitude of factors that contribute to cancer drug resistance. Mathematical modeling studies in particular have been used to explore both broad and detailed aspects of cancer drug resistance, as reviewed in [43,7,25]. The fundamental ques...

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“…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.…”

Section: Introductionmentioning

confidence: 99%

Emergence of cytotoxic resistance in cancer cell populations*

Lorenzi

Chisholm

Lorz

et al. 2015

ITM Web of Conferences

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Abstract. We formulate an individual-based model and an integro-differential model of phenotypic evolution, under cytotoxic drugs, in a cancer cell population structured by the expression levels of survival-potential and proliferation-potential. We apply these models to a recently studied experimental system. Our results suggest that mechanisms based on fundamental laws of biology can reversibly push an actively-proliferating, and drug-sensitive, cell population to transition into a weakly-proliferative and drug-tolerant state, which will eventually facilitate the emergence of more potent, proliferating and drug-tolerant cells.

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The Role of Cell Density and Intratumoral Heterogeneity in Multidrug Resistance

Cited by 66 publications

References 23 publications

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

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

A mathematical approach to differentiate spontaneous and induced evolution to drug resistance during cancer treatment

Emergence of cytotoxic resistance in cancer cell populations*

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