Figure 5.

Mechanisms of action of TMZ and Val-083. Expression of MGMT effectively removes the O⁶-guanine methylation induced by TMZ exposure, which allows cell survival. Lack of MGMT allows the formation of mismatches in the next replication round, which leads to the generation of double DNA-strand breaks mediated by the MMR machinery. The accumulation of double-strand breaks ultimately lead to cell death. However, defects in the MMR pathway paves the way for the accumulation of unresolved mismatches, which allows cell survival and a hypermutation phenotype. In the case of Val-083, there is a formation of interstrand adducts, that are not resolved by MGMT, and lead to cytotoxicity independently of MMR status.