MGMT expression predicts PARP-mediated resistance to temozolomide
Menée in vitro et in vivo, cette étude suggère l'intérêt de mesurer l'expression de MGMT pour prédire la réponse au témozolomide en combinaison avec un inhibiteur de PARP dans le traitement des patients atteints d'un mélanome
Melanoma and other solid cancers are frequently resistant to chemotherapies based on DNA alkylating agents such as dacarbazine and temozolomide (TMZ). 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 TMZ resistance, but co-targeting 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 TMZ and PARP inhibitors, while MGMT-deficient cells do not. In melanoma cells TMZ induced an anti-proliferative senescent response, which was greatly enhanced by PARP-inhibitors in MGMT-positive cells. In summary, we provide compelling evidence to suggest that the stratification of cancer patients upon the MGMT status would enhance the success of combination treatments using TMZ and PARP inhibitors.
Molecular Cancer Therapeutics , résumé, 2015