title: MGMT Expression Predicts PARP-Mediated Resistance to Temozolomide.
abstract: Melanoma and other solid cancers are frequently resistant to chemotherapies based on DNA alkylating agents such as dacarbazine and temozolomide. As a consequence, clinical responses are generally poor. Such resistance is partly due to the ability of cancer cells to use a variety of DNA repair enzymes to maintain cell viability. Particularly, the expression of MGMT has been linked to temozolomide resistance, but cotargeting MGMT has proven difficult due to dose-limiting toxicities. Here, we show that the MGMT-mediated resistance of cancer cells is profoundly dependent on the DNA repair enzyme PARP. Both in vitro and in vivo, we observe that MGMT-positive cancer cells strongly respond to the combination of temozolomide and PARP inhibitors (PARPi), whereas MGMT-deficient cells do not. In melanoma cells, temozolomide induced an antiproliferative senescent response, which was greatly enhanced by PARPi in MGMT-positive cells. In summary, we provide compelling evidence to suggest that the stratification of patients with cancer upon the MGMT status would enhance the success of combination treatments using temozolomide and PARPi.
authors.affiliation: Manchester Cancer Research Centre, The University of Manchester, Michael Smith Building, Oxford Road, Manchester, United Kingdom.
authors.forename: Oihane
authors.initials: O
authors.lastname: Erice
authors.affiliation: Manchester Cancer Research Centre, The University of Manchester, Michael Smith Building, Oxford Road, Manchester, United Kingdom.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Smith
authors.affiliation: Edinburgh Cancer Research UK Centre and MRC Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Rachel
authors.initials: R
authors.lastname: White
authors.affiliation: Manchester Cancer Research Centre, The University of Manchester, Michael Smith Building, Oxford Road, Manchester, United Kingdom.
authors.forename: Ibai
authors.initials: I
authors.lastname: Goicoechea
authors.affiliation: Manchester Cancer Research Centre, The University of Manchester, Michael Smith Building, Oxford Road, Manchester, United Kingdom.
authors.forename: Jorge
authors.initials: J
authors.lastname: Barriuso
authors.affiliation: Divisions of Molecular Pathology and Cancer Therapeutics, Institute of Cancer Research, Sutton, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Jones
authors.affiliation: Centre for Occupational and Environmental Health, The University of Manchester, Stopford Building, Manchester, United Kingdom.
authors.forename: Geoffrey P
authors.initials: GP
authors.lastname: Margison
authors.affiliation: Edinburgh Cancer Research UK Centre and MRC Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Acosta
authors.affiliation: Manchester Cancer Research Centre, The University of Manchester, Michael Smith Building, Oxford Road, Manchester, United Kingdom. I.Arozarena@hud.ac.uk Claudia.Wellbrock@manchester.ac.uk.
authors.forename: Claudia
authors.initials: C
authors.lastname: Wellbrock
authors.affiliation: Manchester Cancer Research Centre, The University of Manchester, Michael Smith Building, Oxford Road, Manchester, United Kingdom. I.Arozarena@hud.ac.uk Claudia.Wellbrock@manchester.ac.uk.
authors.forename: Imanol
authors.initials: I
authors.lastname: Arozarena
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000378:metabolism*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D011065:Poly(ADP-ribose) Polymerases; D045643:DNA Repair Enzymes; D000077204:Temozolomide