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26.01.2024 | Research

Circadian regulation of MGMT expression and promoter methylation underlies daily rhythms in TMZ sensitivity in glioblastoma

verfasst von: Maria F. Gonzalez-Aponte, Anna R. Damato, Laura Lucía Trebucq, Tatiana Simon, Sandra P. Cárdenas-García, Kevin Cho, Gary J. Patti, Diego A. Golombek, Juan José Chiesa, Joshua B. Rubin, Erik D. Herzog

Erschienen in: Journal of Neuro-Oncology | Ausgabe 3/2024

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Abstract

Background

Glioblastoma (GBM) is the most common primary brain tumor in adults. Despite extensive research and clinical trials, median survival post-treatment remains at 15 months. Thus, all opportunities to optimize current treatments and improve patient outcomes should be considered. A recent retrospective clinical study found that taking TMZ in the morning compared to the evening was associated with a 6-month increase in median survival in patients with MGMT-methylated GBM. Here, we hypothesized that TMZ efficacy depends on time-of-day and O⁶-Methylguanine-DNA Methyltransferase (MGMT) activity in murine and human models of GBM.

Methods and results

In vitro recordings using real-time bioluminescence reporters revealed that GBM cells have intrinsic circadian rhythms in the expression of the core circadian clock genes Bmal1 and Per2, as well as in the DNA repair enzyme, MGMT. Independent measures of MGMT transcript levels and promoter methylation also showed daily rhythms intrinsic to GBM cells. These cells were more susceptible to TMZ when delivered at the daily peak of Bmal1 transcription. We found that in vivo morning administration of TMZ also decreased tumor size and increased body weight compared to evening drug delivery in mice bearing GBM xenografts. Finally, inhibition of MGMT activity with O⁶-Benzylguanine abrogated the daily rhythm in sensitivity to TMZ in vitro by increasing sensitivity at both the peak and trough of Bmal1 expression.

Conclusion

We conclude that chemotherapy with TMZ can be dramatically enhanced by delivering at the daily maximum of tumor Bmal1 expression and minimum of MGMT activity and that scoring MGMT methylation status requires controlling for time of day of biopsy.

Graphical abstract

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Titel: Circadian regulation of MGMT expression and promoter methylation underlies daily rhythms in TMZ sensitivity in glioblastoma
verfasst von: Maria F. Gonzalez-Aponte
Anna R. Damato
Laura Lucía Trebucq
Tatiana Simon
Sandra P. Cárdenas-García
Kevin Cho
Gary J. Patti
Diego A. Golombek
Juan José Chiesa
Joshua B. Rubin
Erik D. Herzog
Publikationsdatum: 26.01.2024
Verlag: Springer US
Erschienen in: Journal of Neuro-Oncology / Ausgabe 3/2024
Print ISSN: 0167-594X
Elektronische ISSN: 1573-7373
DOI: https://doi.org/10.1007/s11060-023-04535-9

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