Toward understanding of the role of reversibility of phenotypic switching in the evolution of resistance to therapy

Horváth, Denis; Brutovsky, B.

doi:10.1016/j.physleta.2018.03.052

Cited by 4 publications

(3 citation statements)

References 79 publications

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“…According to the heterogeneous distribution of lipids in the tumor, the cell response and signaling pathways triggered by PKC could also be heterogeneous. Moreover, cells may change their phenotype in response to treatments [34]. However, in the present study, distancebased analysis led to the identification of Gö 6976 and hypericin as unique molecules.…”

Section: Molecule In 10% Fbs In 2% Ugmentioning

confidence: 65%

Selection of Unique Molecules for Cancer Treatment by Distance-Based Method: Hypericin Effect on Respiratory Chain

2021

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The heterogeneous composition of tumors presents a significant obstacle to the selection of a single molecule as a potential universal inhibitor of tumor growth. Lipid signaling and cellular metabolism have become the main targets of anticancer treatment in recent years. The protein kinase C (PKC) regulators Gö6976, rottlerin, hypericin, and phorbol myristyl acetate have been identified as agents affecting cellular metabolism. Measurable parameters describing metabolism, endocytosis, and respiration were subjected to a distance-based computational procedure for higher dimensions to complement and extend the knowledge gained from experimental data. The mutual distances of the parameters of the substances applied to the cancer cells in the presence and absence of lipids were calculated within the Lp spaces. The distance-based methods and comparisons of the generalized distances suggested to us the exceptional role of hypericin in heterogeneous systems. Furthermore, our results are confirmed by Western blotting of the levels of respiratory chain proteins and enzymes active in oxidative stress defense in cancer cell monolayers and spheroids. PKCα and PKCδ have been studied for lipid-activated cell signaling. In this study, we attempt to apply the concept of parametric distance in cell signal transduction and activation where the above methods have not yet been used.

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Section: Molecule In 10% Fbs In 2% Ugmentioning

confidence: 65%

Selection of Unique Molecules for Cancer Treatment by Distance-Based Method: Hypericin Effect on Respiratory Chain

2021

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“…Rather, adaptive phenotypic changes can arise without an associated genetic mutation. Such phenotypic heterogeneity has been extensively studied as a possible mechanism of treatment resistance [7,8,[10][11][12][13][14]. For example, chemotherapy has been shown to induce a transient drug-tolerant phenotype in breast cancer cell lines such that re-sensitisation occurs following cessation of therapy [15,16], an example of phenotypic plasticity [17].…”

Section: Introductionmentioning

confidence: 99%

The role of memory in non-genetic inheritance and its impact on cancer treatment resistance

et al. 2021

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Intra-tumour heterogeneity is a leading cause of treatment failure and disease progression in cancer. While genetic mutations have long been accepted as a primary mechanism of generating this heterogeneity, the role of phenotypic plasticity is becoming increasingly apparent as a driver of intra-tumour heterogeneity. Consequently, understanding the role of this plasticity in treatment resistance and failure is a key component of improving cancer therapy. We develop a mathematical model of stochastic phenotype switching that tracks the evolution of drug-sensitive and drug-tolerant subpopulations to clarify the role of phenotype switching on population growth rates and tumour persistence. By including cytotoxic therapy in the model, we show that, depending on the strategy of the drug-tolerant subpopulation, stochastic phenotype switching can lead to either transient or permanent drug resistance. We study the role of phenotypic heterogeneity in a drug-resistant, genetically homogeneous population of non-small cell lung cancer cells to derive a rational treatment schedule that drives population extinction and avoids competitive release of the drug-tolerant sub-population. This model-informed therapeutic schedule results in increased treatment efficacy when compared against periodic therapy, and, most importantly, sustained tumour decay without the development of resistance.

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“…Rather, adaptive phenotypic change can arise without an associated genetic mutation. Such phenotypic heterogeneity has been extensively studied as a possible mechanism of treatment resistance [7,8,[10][11][12][13][14]. For example, chemotherapy has been shown to induce a transient drug-tolerant phenotype in breast cancer cell lines such that re-sensitisation occurs following cessation of therapy [15,16], an example of phenotypic plasticity [17].…”

Section: Introductionmentioning

confidence: 99%

The role of memory in non-genetic inheritance and its impact on cancer treatment resistance

Cassidy

Nichol

Robertson-Tessi

et al. 2021

Preprint

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Intra-tumour heterogeneity is a leading cause of treatment failure and disease progression in cancer. While genetic mutations have long been accepted as a primary mechanism of generating this heterogeneity, the role of phenotypic plasticity is becoming increasingly apparent as a driver of intra-tumour heterogeneity. Consequently, understanding the role of plasticity in treatment resistance and failure is a key component of improving cancer therapy. We develop a mathematical model of stochastic phenotype switching that tracks the evolution of drug-sensitive and drug-tolerant subpopulations to clarify the role of phenotype switching on population growth rates and tumour persistence. By including cytotoxic therapy in the model, we show that, depending on the strategy of the drug-tolerant subpopulation, stochastic phenotype switching can lead to either transient or permanent drug resistance. We study the role of phenotypic heterogeneity in a drug-resistant, genetically homogeneous population of non-small cell lung cancer cells to derive a rational treatment schedule that drives population extinction and avoids competitive release of the drug-tolerant sub-population. This model-informed therapeutic schedule results in increased treatment efficacy when compared against periodic therapy, and, most importantly, sustained tumour decay without the development of resistance.

show abstract

Toward understanding of the role of reversibility of phenotypic switching in the evolution of resistance to therapy

Cited by 4 publications

References 79 publications

Selection of Unique Molecules for Cancer Treatment by Distance-Based Method: Hypericin Effect on Respiratory Chain

Selection of Unique Molecules for Cancer Treatment by Distance-Based Method: Hypericin Effect on Respiratory Chain

The role of memory in non-genetic inheritance and its impact on cancer treatment resistance

The role of memory in non-genetic inheritance and its impact on cancer treatment resistance

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