MGMT Expression Predicts PARP-Mediated Resistance to Temozolomide

Oihane Erice, Michael P Smith, Rachel White, Ibai Goicoechea, Jorge Barriuso, Chris Jones, Geoffrey P Margison, Juan C Acosta, Claudia Wellbrock, Imanol Arozarena

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

Original languageEnglish
Pages (from-to)1236-46
Number of pages11
JournalMolecular Cancer Therapeutics
Issue number5
Publication statusPublished - Jul 2015

Keywords / Materials (for Non-textual outputs)

  • Animals
  • Antineoplastic Agents, Alkylating
  • Cell Line, Tumor
  • Cell Proliferation
  • DNA Modification Methylases
  • DNA Repair Enzymes
  • Dacarbazine
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Melanoma
  • Mice
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Poly(ADP-ribose) Polymerases
  • Tumor Suppressor Proteins


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