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

被引：14
作者：
Cassidy T. [1 ]
Nichol D. [2 ]
Robertson-Tessi M. [3 ]
Craig M. [4 ,5 ]
Anderson A.R.A. [3 ]
机构：
[1] Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM
[2] Evolutionary Genomics and Modelling Lab, Centre for Evolution and Cancer, The Institute of Cancer Research, London
[3] Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center, Tampa, FL
[4] Département de Mathématiques et de Statistique, Université de Montréal, Montreal
[5] CHU Sainte-Justine, Montreal
来源：
PLoS Computational Biology | 2021年 / 17卷 / 08期
基金：
加拿大自然科学与工程研究理事会; 美国国家卫生研究院;
关键词：
TC was partially supported by the Natural Sciences and Research Council of Canada (NSERC) through the PGS-D program and NIH grants R01-AI116868 and R01-OD011095. Portions of this work were performed under the auspices of the U.S. Department of Energy under contract 89233218CNA000001. DN received no specific funding for this work. MC was funded by NSERC Discovery grant and Discovery Launch Supplement RGPIN-2018-04546. MRT and ARAA were funded by the Cancer Systems Biology Consortium and the Physical Sciences Oncology Network at the National Cancer Institute; through grants U01CA232382 and U54CA193489. Support from the Moffitt Center of Excellence for Evolutionary Therapy. The funders had no role in study design; data collection and analysis; decision to publish; or preparation of the manuscript. Portions of this work were completed while TC; DN; and ARAA participated in the thematic semester in Mathematical Biology at the Institut Mittag-Leffler. TC is grateful for many useful conversations with Tony Humphries;
D O I：
10.1371/journal.pcbi.1009348
中图分类号：
学科分类号：
摘要：
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. © This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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