Molecular analysis of the dual targeting of the epidermal growth factor receptor and the O⁶-methylguanine-DNA methyltransferase with a double arm hybrid molecule.

ABSTRACT: Disordered expression of the epidermal growth factor receptor (EGFR) has been associated with induction of DNA repair genes (e.g. XRCC1, ERCC1) and resistance to radiation and genotoxic drugs. However, our previous work showed that EGFR inhibition did not affect O⁶-methylguanine-DNA methyltransferase (MGMT)-mediated resistance. In order to block uncoupled events associated with EGFR and MGMT, we designed MR30, a single molecule termed "combi-molecule" that contains a quinazoline arm targeted to EGFR and an O⁶-benzylguanine (O⁶-BG) moiety to block MGMT. Molecular analysis of the mechanism of action of its two arms showed that: (a) it could block EGFR phosphorylation, (b) down-regulate the RAF-MAPK and the PI3K-AKT pathways, and (c) covalently modify MGMT thr

SUBMITTER: Rupp M 

PROVIDER: S-EPMC6205551 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature