Fig. 6. Model.

Under conditions where MGMT is expressed (MGMT-U), both EGFRvIII- and EGFRvIII+ GBM cells are resistant to TMZ. This is because MGMT removes the O⁶MeG lesions and therefore prevents replication-dependent induction of DNA DSB. EGFRvIII− cells which do not express MGMT (MGMT-M) display moderate TMZ sensitivity, because O⁶MeG lesions are converted through futile MMR cycles into DSB. In MGMT deficient (MGMT-M) cells expressing EGFRvIII, MAPK signaling is activated, which leads to upregulation of MMR protein expression. This leads to a more efficient conversion of O⁶MeG lesions into lethal DSB and, consequently, to increased TMZ sensitivity.