Research Papers:

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

Martin Rupp, Zhor Senhaji Mouhri, Christopher Williams and Bertrand J. Jean-Claude _

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Oncotarget. 2018; 9:35041-35055. https://doi.org/10.18632/oncotarget.25120

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Martin Rupp1, Zhor Senhaji Mouhri1, Christopher Williams2 and Bertrand J. Jean-Claude1

1Cancer Drug Research Laboratory, Department of Medicine, Division of Medical Oncology, The Research Institute of the McGill University Health Center/Glen Hospital, Montreal, QC, H4A 3J1, Canada

2Scientific Support, Chemical Computing Group Inc., Montreal, QC, H3A 2R7, Canada

Correspondence to:

Bertrand J. Jean-Claude, email: [email protected]

Keywords: EGFR; MGMT; combi-molecule; kinase inhibition; combination chemotherapy

Received: January 12, 2018     Accepted: March 06, 2018     Published: October 12, 2018


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 through S-benzylation, as confirmed by MALDI analysis of a direct binding assay with isolated MGMT, (d) it induced a dose-dependent down-regulation of MGMT in lung and melanoma cells. The pleiotropic mechanism of action of MR30 culminated into strong growth inhibition (IC50: 0.018-6.02 μM), with superior activity when compared with an equimolar combination of gefitinib (a clinical EGFR inhibitor) and O6-BG (a known MGMT inhibitor). Pulse exposure experiments were required to attenuate the contribution of EGFR inhibition to the strong potency of MR30, thereby allowing to achieve the dose level required to sensitize cells to temozolomide (TMZ). Indeed, MR30 significantly sensitized EGFR-MGMT co-expressing cells to TMZ (p<0.05-0.0001). The results in toto suggest that MR30 is the first prototype of agents that may be used against tumours addicted to EGFR and to sensitize resistant tumours co-expressing EGFR and MGMT to TMZ.

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