Epigenetic instability may alter cell state transitions and anticancer drug resistance.
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...
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| Autores principales: | , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Public Library of Science (PLoS)
2021
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/6c9e006cf9054e7b99c24469fa567e8f |
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| Sumario: | 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. |
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