Background: Temozolomide is used as frontline chemotherapy in the management
of glioblastoma multiforme (GBM); however, its clinical utility is limited by the
occurrence of significant resistance, majorly caused due to direct DNA repair. O6-
methylguanine-DNA-methyltransferase (MGMT), a DNA repair protein, mediates this direct
repair pathway and reverses the activity of temozolomide.
Methods: We characterize and underscore the functional relevance and molecular aspects
of MGMT in the development of sensitivity/resistance to temozolomide treatment. We review
early translational, as well as clinical, evidence for the role of MGMT in mediating
temozolomide resistance in vitro in cell lines, in vivo in small animals as well as in GBM
Results: Various approaches have been delineated to mitigate MGMT-induced temozolomide
resistance. The most promising means in discovery biology appears to be the
co-administration of MGMT inhibitors such as O6 benzyl guanine or lomeguatrib. Surprisingly,
the validation of these pharmacologic inhibitors to assess the reversal of chemoresistance
by appropriately designed safety and efficacy trials in combination with temozolomide
is yet to be demonstrated.
Conclusion: Taken together, given the regulation of temozolomide resistance by MGMT,
intermediate and late discovery groups may focus their efforts on pharmacologic inhibition
of MGMT, singly or in combination with radiotherapy or immunotherapy, to combat
temozolomide resistance in GBM patients. In addition, one may speculate that the combined
clinical use of temozolomide with a drug regulator-approved MGMT inhibitor as
well as an immune checkpoint inhibitor such as nivolumab may prove beneficial. Future
studies may also investigate any inter-ethnic variability in population pharmacogenetics of
MGMT and pharmacometric approaches to optimize cancer precision medicine.