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

Tyler Cassidy , Daniel Nichol, Mark Robertson-Tessi, Morgan Craig, Alexander R. A. Anderson

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.

Introduction
Intra-tumour heterogeneity is a leading driver of cancer treatment failure [1–3]. The genetic instability and high proliferative capacity typical of cancer cells induces a genetically heterogenous population in which resistance-conferring mutations can arise and expand during the selective pressure of therapy.

In recent years, evolutionarily-informed cancer therapy regimens have arisen as a potential strategy to delay the emergence of drug resistance. Adaptive therapies exploit competition between clonal populations by incorporating periods without therapy wherein resistant subclones, which are often assumed to have a fitness cost in the absence of treatment, can be outcompeted by drug-sensitive clones.

Materials and methods

Non-small cell lung cancer data
We used the previously published in vitro growth assay data from Craig et al. [7] to parametrize our mathematical model.

In the untreated experiments, Craig et al. [7] cultured a genotypically homogeneous population of NSCLC cells for 7 days. In the treated experiments, after 72 hours of growth in untreated medium, the authors bathed the population of cells in a constant and lethal concentration of one of three chemotherapeutics (docetaxel, afatinib, or bortezomib) and counted the number of surviving cells

Discussion
Despite the introduction of novel targeted therapies and increased characterisations of individual patient’s genetic landscapes, drug resistance continues to drive treatment failure. This suggests that identifying and understanding non-genetic factors contributing to drug therapy tolerance is crucial to providing better care.

Acknowledgments:
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.

Citation: Cassidy T, Nichol D, Robertson-Tessi M, Craig M, Anderson ARA (2021) The role of memory in non-genetic inheritance and its impact on cancer treatment resistance. PLoS Comput Biol 17(8): e1009348. https://doi.org/10.1371/journal.pcbi.1009348

Editor: Dominik Wodarz, University of California Irvine, UNITED STATES

Received: March 1, 2021; Accepted: August 11, 2021; Published: August 30, 2021.

Copyright: 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.

Data Availability: The data underlying the results presented in the study are available in the supplementary material of Craig et al. (2019), DOI: 10.1371/journal.pcbi.1007278.

Funding: 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.

Competing interests: The authors have declared that no competing interests exist.

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