RDNA-12. ATR INHIBITOR VE-822 IS A NOVEL RADIO- SENSITIZER FOR GLIOMA
| Autor: | Bipasha Mukherjee, Varun Sadaphal, Eliot Fletcher, Monica Lou, Vineshkumar Thidil Puliyappadamba, Ram Shankar Mani, Sandeep Burma, Xiang Li |
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| Rok vydání: | 2018 |
| Předmět: | |
| Zdroj: | Neuro-Oncology. 20:vi224-vi224 |
| ISSN: | 1523-5866 1522-8517 |
| DOI: | 10.1093/neuonc/noy148.927 |
| Popis: | Glioblastomas (GBM) are lethal brain tumors for which surgical resection, treatment with ionizing radiation (IR) and concurrent administration of Temozolomide (TMZ) is the mainstay of therapy. These tumors are extremely radioresistant, and resistance to radiation is one of the primary causes of therapy failure. Therefore, there is an urgent need to overcome radioresistance in GBM in order to develop effective therapies for treatment. IR induces double strand breaks (DSBs) in the DNA, and these are extremely deleterious lesions that can be repaired either by error-prone non-homologous end joining (NHEJ) or the error-free homologous recombination (HR) pathway. Our laboratory has shown that the 5’-3’ exonuclease EXO1 is crucial for DNA end resection and accurate repair pathway choice. We have previously shown that EXO1 is phosphorylated and activated by CDKs 1 and 2 in the S and G2 phases of the cell cycle which results in promotion of error-free HR as well as activation of the ATR kinase. Once activated, ATR phosphorylates EXO1 and targets it for degradation thereby preventing hyper-resection and genomic instability. Therefore, we hypothesized that ATR inhibitors could augment radiotherapy by stabilizing EXO1. Indeed, we find that that a specific ATR inhibitor - VE-822 - blocks IR-induced EXO1 degradation in a panel of GBM cell lines resulting in hyper-resection and attenuation of HR. Hence, treatment with VE-822 sensitizes GBM lines to IR in vitro. In vivo, we show that the drug can cross the blood-brain barrier and, in conjunction with IR, can block DNA repair in intracranial tumors, attenuate tumor growth and consequently extend survival of tumor-bearing mice. Our results indicate that negative regulation of EXO1 by ATR is critical for optimal DSB repair, and that this connection can be subverted by ATR inhibitors in order to improve GBM radiotherapy in the clinic. |
| Databáze: | OpenAIRE |
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