Epigenetic instability may alter cell state transitions and anticancer drug resistance

PLoS Comput Biol. 2021 Aug 23;17(8):e1009307. doi: 10.1371/journal.pcbi.1009307. eCollection 2021 Aug.

Abstract

Drug resistance is a significant obstacle to successful and durable anti-cancer therapy. Targeted therapy is often effective during early phases of treatment; however, eventually cancer cells adapt and transition to drug-resistant cells states rendering the treatment ineffective. It is proposed that cell state can be a determinant of drug efficacy and manipulated to affect the development of anticancer drug resistance. In this work, we developed two stochastic cell state models and an integrated stochastic-deterministic model referenced to brain tumors. The stochastic cell state models included transcriptionally-permissive and -restrictive states based on the underlying hypothesis that epigenetic instability mitigates lock-in of drug-resistant states. When moderate epigenetic instability was implemented the drug-resistant cell populations were reduced, on average, by 60%, whereas a high level of epigenetic disruption reduced them by about 90%. The stochastic-deterministic model utilized the stochastic cell state model to drive the dynamics of the DNA repair enzyme, methylguanine-methyltransferase (MGMT), that repairs temozolomide (TMZ)-induced O6-methylguanine (O6mG) adducts. In the presence of epigenetic instability, the production of MGMT decreased that coincided with an increase of O6mG adducts following a multiple-dose regimen of TMZ. Generation of epigenetic instability via epigenetic modifier therapy could be a viable strategy to mitigate anticancer drug resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / therapeutic use*
  • Antineoplastic Agents, Alkylating / therapeutic use*
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / genetics
  • Brain Neoplasms / pathology
  • Drug Resistance, Neoplasm / genetics*
  • Epigenesis, Genetic*
  • Humans
  • Temozolomide / therapeutic use*

Substances

  • Antineoplastic Agents
  • Antineoplastic Agents, Alkylating
  • Temozolomide

Grant support

Funding from the State University of New York Empire Innovation program is acknowledged for support of AS PhD. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.