Epigenetic instability may alter cell state transitions and anticancer drug resistance.

Autor: Anshul Saini, James M Gallo
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: PLoS Computational Biology, Vol 17, Iss 8, p e1009307 (2021)
Druh dokumentu: article
ISSN: 1553-734X
1553-7358
DOI: 10.1371/journal.pcbi.1009307
Popis: 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.
Databáze: Directory of Open Access Journals
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje