Cobler Lara, Zhang Hui, Suri Poojan, Park Catherine, Timmerman Luika A
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
Department of Radiation Oncology, University of California, San Francisco, CA, USA.
Oncotarget. 2018 Aug 17;9(64):32280-32297. doi: 10.18632/oncotarget.25794.
About 3 million US cancer patients and 1.7 million EU cancer patients received multiple doses of radiation therapy (RT) in 2012, with treatment duration limited by normal adjacent tissue damage. Tumor-specific sensitization could allow treatment with lower radiation doses, reducing normal tissue damage. This is a longstanding, largely unrealized therapeutic goal. The cystine:glutamate exchanger xCT is expressed on poor prognosis subsets of most solid tumors, but not on most normal cells. xCT provides cells with environmental cystine for enhanced glutathione synthesis. Glutathione is used to control reactive oxygen species (ROS), which are therapeutic effectors of RT. We tested whether xCT inhibition would sensitize xCT tumor cells to ionizing radiation. We found that pretreatment with the xCT inhibitor erastin potently sensitized xCT but not xCT cells, and in xenograft. Similarly, targeted gene inactivation also sensitized cells, and both modes of sensitization were overcome by glutathione supplementation. Sensitization prolongs DNA damage signaling, increases genome instability, and enhances cell death, revealing an unforeseen role for cysteine in genome integrity maintenance. We conclude that an xCT-specific therapeutic would provide tumor-specific sensitization to RT, allowing treatment with lower radiation doses, and producing far fewer side effects than other proposed sensitizers. Our data speaks to the need for the rapid development of such a drug.
2012年，约300万美国癌症患者和170万欧盟癌症患者接受了多剂量放射治疗（RT），治疗持续时间受相邻正常组织损伤的限制。肿瘤特异性增敏可使患者接受较低剂量的放射治疗，减少正常组织损伤。这是一个长期以来基本未实现的治疗目标。胱氨酸：谷氨酸交换体xCT在大多数实体瘤预后较差的亚群中表达，但在大多数正常细胞中不表达。xCT为细胞提供环境胱氨酸以增强谷胱甘肽合成。谷胱甘肽用于控制活性氧（ROS），而ROS是放射治疗的效应因子。我们测试了抑制xCT是否会使表达xCT的肿瘤细胞对电离辐射敏感。我们发现，用xCT抑制剂艾拉斯汀预处理可有效使表达xCT的肿瘤细胞增敏，但对不表达xCT的细胞无效，在异种移植模型中也是如此。同样，靶向基因失活也使细胞增敏，且两种增敏方式均可通过补充谷胱甘肽来克服。增敏作用延长了DNA损伤信号传导，增加了基因组不稳定性，并增强了细胞死亡，揭示了半胱氨酸在维持基因组完整性中未被预见的作用。我们得出结论，一种针对xCT的疗法将为放射治疗提供肿瘤特异性增敏作用，使患者能够接受更低剂量的放射治疗，且产生的副作用远少于其他已提出的增敏剂。我们的数据表明需要迅速开发这样一种药物。
