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: Oihane Erice, Michael P Smith, Rachel White, Ibai Goicoechea, Jorge Barriuso, Chris Jones, Geoffrey P Margison, Juan C Acosta, Claudia Wellbrock, Imanol Arozarena
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 14 Issue 5 Pg. 1236-46 (May 2015) ISSN: 1538-8514 [Electronic] United States
• PMID: 25777962 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents, Alkylating
• Poly(ADP-ribose) Polymerase Inhibitors
• Tumor Suppressor Proteins
• Dacarbazine
• DNA Modification Methylases
• MGMT protein, human
• Poly(ADP-ribose) Polymerases
• DNA Repair Enzymes
• Temozolomide

Topics

• Animals
• Antineoplastic Agents, Alkylating (administration & dosage, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• DNA Modification Methylases (metabolism)
• DNA Repair Enzymes (metabolism)
• Dacarbazine (administration & dosage, analogs & derivatives, pharmacology)
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Melanoma (drug therapy, metabolism)
• Mice
• Poly(ADP-ribose) Polymerase Inhibitors (administration & dosage, pharmacology)
• Poly(ADP-ribose) Polymerases (metabolism)
• Temozolomide
• Tumor Suppressor Proteins (metabolism)