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.

Examining the efficacy of localised gemcitabine therapy for the treatment of pancreatic cancer using a hybrid agent-based model

“…Lastly, while we did not consider gemcitabine resistance in our model, it does occur in PDAC [3, 4]. A simple extension of the model could consider the impact of resistance on the performance of therapy like other works on resistance of chemotherapeutics using mathematical models [22, 92].…”

Understanding and leveraging phenotypic plasticity during metastasis formation

“…theoretical studies to treat phenotypically heterogeneous tumors (Viossat and Noble, 2021;Raatz et al, 2021;Cassidy et al, 2021) with some experiments to support them (Li and Thirumalai, 2022). These strategies aim to remove or reduce the tumor burden and delay tumor relapse.…”

Scales of Cancer Evolution: Selfish Genome or Cooperating Cells?

“…Presently, phenotypic plasticity is attracting much attention, as the intraclonal variability in phenotypic characteristics of isogenic cancer cells affects cancer progression and its response to treatment [62][63][64]. Evidence of cancer cell plasticity motivates the effort to stimulate (or prevent) specific phenotype switching purposefully as a therapeutic strategy [65][66][67]. However, it requires not only deep knowledge of molecular mechanisms responsible for the cancer cell plasticity [68], but understanding its dynamics at a conceptual level as well.…”