Inhibition of DNA double-strand break repair by the dual PI3K/mTOR inhibitor NVP-BEZ235 as a strategy for radiosensitization of glioblastoma.
Inhibition of DNA double-strand break repair by the dual PI3K/mTOR inhibitor NVP-BEZ235 as a strategy for radiosensitization of glioblastoma.
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DOI：
10.1158/1078-0432.ccr-13-1607
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发表时间：
2014-03-01
期刊：
影响因子：
--
通讯作者：
Burma S
中科院分区：
文献类型：
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作者：
Gil del Alcazar CR;Hardebeck MC;Mukherjee B;Tomimatsu N;Gao X;Yan J;Xie XJ;Bachoo R;Li L;Habib AA;Burma S
DNA损伤反应（DDR）抑制剂对许多癌症（包括胶质母细胞瘤（GBM））的放射增敏具有很大的潜力，胶质母细胞瘤是一种对放射和化学具有极强抗性的脑肿瘤。目前，没有DNA双链断裂（DSB）修复抑制剂已成功治疗GBM。我们的实验室先前已经证明，双重PI 3 K/mTOR抑制剂NVP-BEZ 235可以在体外有效地抑制两种中心DDR激酶DNA-PKcs和ATM。在这里，我们测试了NVP-BEZ 235是否也可以在体内抑制肿瘤中的ATM和DNA-PKcs，并评估了其作为临床前小鼠GBM模型中的放射和化学增敏剂的潜力。通过在皮下和原位GBM模型中跟踪肿瘤生长来测试NVP-BEZ 235的放射增敏作用。使用放射抗性U87-vIII胶质瘤细胞系和GBM 9神经球在裸鼠中产生肿瘤。然后用电离辐射（IR）和/或NVP-BEZ 235处理这些肿瘤，并分析DNA-PKcs和ATM活化、DSB修复抑制和生长衰减。NVP-BEZ 235有效地抑制DNA-PKcs和ATM激酶，并减弱肿瘤中IR诱导的DNA损伤的修复。这导致了显著的肿瘤放射增敏作用，延长了脑肿瘤小鼠的生存期。值得注意的是，与正常脑组织相比，肿瘤显示出更高的DSB负荷。NVP-BEZ 235还使皮下肿瘤的子集对替莫唑胺敏感，替莫唑胺是一种常规与IR同时用于治疗GBM的药物。这些结果表明，通过将IR与NVP-BEZ 235等强效且生物可利用的DNA修复抑制剂相结合，有可能显着改善GBM治疗。
Inhibitors of the DNA damage response (DDR) have great potential for radiosensitization of numerous cancers including glioblastomas (GBM), which are extremely radio- and chemo-resistant brain tumors. Currently, there are no DNA double-strand break (DSB) repair inhibitors that have been successful in treating GBM. Our lab has previously demonstrated that the dual PI3K/mTOR inhibitor NVP-BEZ235 can potently inhibit the two central DDR kinases, DNA-PKcs and ATM, in vitro. Here, we tested whether NVP-BEZ235 could also inhibit ATM and DNA-PKcs in tumors in vivo and assessed its potential as a radio- and chemo-sensitizer in pre-clinical mouse GBM models. The radiosensitizing effect of NVP-BEZ235 was tested by following tumor growth in subcutaneous and orthotopic GBM models. Tumors were generated using the radioresistant U87-vIII glioma cell line and GBM9 neurospheres in nude mice. These tumors were then treated with ionizing radiation (IR) and/or NVP-BEZ235 and analyzed for DNA-PKcs and ATM activation, DSB repair inhibition, and attenuation of growth. NVP-BEZ235 potently inhibited both DNA-PKcs and ATM kinases and attenuated the repair of IR-induced DNA damage in tumors. This resulted in striking tumor radiosensitization, which extended the survival of brain tumor-bearing mice. Notably, tumors displayed a higher DSB-load when compared to normal brain tissue. NVP-BEZ235 also sensitized a subset of subcutaneous tumors to temozolomide, a drug routinely used concurrently with IR for the treatment of GBM. These results demonstrate that it may be possible to significantly improve GBM therapy by combining IR with potent and bioavailable DNA repair inhibitors like NVP-BEZ235.