Contribution of ATM and ATR to the resistance of glioblastoma and malignant melanoma cells to the methylating anticancer drug temozolomide
Menée sur des lignées cellulaires de glioblastome et de mélanome, cette étude suggère que l'inhibition des kinases ATM et ATR augmente la sensibilité des cellules cancéreuses au témolozomide
The major cytotoxic DNA adduct induced by temozolomide and other methylating agents used in malignant glioma and metastasized melanoma therapy is O6-methylguanine. This primary DNA damage is converted by mismatch repair into secondary lesions, which block replication and in turn induce DNA double-strand breaks that trigger the DNA damage response (DDR). Key upstream players in the DDR are the PI3 kinases ATM and ATR. Here we addressed the question of the importance of ATM and ATR in the cell death response following temozolomide. We show that a) ATM and ATR mutated cells are hypersensitive to temozolomide, b) O6-methylguanine triggers ATM and ATR activation, c) knockdown of ATM and ATR enhances cell kill in gliobalstoma and malignant melanoma cells with a stronger effect in ATR knockdown cells, d) ATR, but not ATM knockdown abolished phosphorylation of H2AX, CHK1 and CHK2 in glioma cells, and e) temozolomide-induced cell death was more prominently enhanced by pharmacological inhibition of CHK1 compared to CHK2. The data suggests that ATM and, even better, ATR inhibition is a useful strategy in sensitizing cancer cells to temozolomide and presumably also other anticancer drugs.
http://mct.aacrjournals.org/content/early/2013/08/17/1535-7163.MCT-13-0136.abstract