Paper Info
Title
The role of memory in non-genetic inheritance and its impact on cancer treatment resistance.
Abstract
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.
Year
DOI
Venue
2021
10.1371/journal.pcbi.1009348
PLoS Comput. Biol.
DocType
Volume
Issue
Journal
17
8
ISSN
Citations 
PageRank 
1553-7358
0
0.34
References 
Authors
0
5
Name
Order
Citations
PageRank
Tyler Cassidy100.68
Daniel Nichol200.34
Mark Robertson-Tessi310.70
Morgan Craig400.34
Alexander R. A. Anderson53610.26