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

Morning administration of TMZ is associated with a 6-month increase in median survival for patients with methylated GBM.

• GBM cells exhibit intrinsic circadian rhythms in the expression of core circadian clock genes and the DNA repair enzyme MGMT.
• Daily rhythms in GBM cells affect their susceptibility to TMZ, with increased sensitivity observed at the peak of transcription.
• In preclinical mouse models, morning TMZ administration decreased tumor size and increased body weight compared to evening administration.
• Inhibition of MGMT activity with O-Benzylguanine eliminated the daily rhythm in sensitivity to TMZ, enhancing susceptibility at all times.

AI simplified