Fig. 9: Model on the impact of clock KOs on TMZ sensitivity. | npj Precision Oncology

Fig. 9: Model on the impact of clock KOs on TMZ sensitivity.

From: Personalized chronotherapy in glioblastoma: integrating circadian profiling and PK–PD modelling to optimize temozolomide timing

Fig. 9

Left panel: TMZ sensitivity was shown to be coinciding with the peak of BMAL1 and BMAL1 and MGMT were shown to stand in an antiphase relationship to each other. MGMT is the main detoxifying enzyme of TMZ and implicating in removing TMZ-mediated methyl groups from DNA thus preventing DNA damage and apoptosis. The model predicts an abolished inhibitory effect of PER2 in the PER2 KO cells, therefore promoting the activation of MGMT by CRY. Additionally, the NR1D1 KO predicts lower BMAL1-dependent inhibition of MGMT. Right panel: PER2 was shown to compete with MDM2 for the binding of p53 and to activate p53 in this process. p53 is induced by DNA damage and induces apoptosis. In the PER2 KO p53 activation following TMZ-mediated DNA damage is expected to be reduced explaining the higher resistance to TMZ. NR1D1 was shown to inhibit DNA damage repair by PARP and BRCA1. In the NR1D1 KO cells DNA damage repair after TMZ exposure is expected to be enhanced contributing to enhanced resistance to TMZ. The figure was created in Biorender.com.

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