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Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma.
Nature Medicine ( IF 58.7 ) Pub Date : 2017-Nov-01 , DOI: 10.1038/nm.4418
Wilson X Mai , Laura Gosa , Veerle W Daniels , Lisa Ta , Jonathan E Tsang , Brian Higgins , W Blake Gilmore , Nicholas A Bayley , Mitra Dehghan Harati , Jason T Lee , William H Yong , Harley I Kornblum , Steven J Bensinger , Paul S Mischel , P Nagesh Rao , Peter M Clark , Timothy F Cloughesy , Anthony Letai , David A Nathanson

Cross-talk among oncogenic signaling and metabolic pathways may create opportunities for new therapeutic strategies in cancer. Here we show that although acute inhibition of EGFR-driven glucose metabolism induces only minimal cell death, it lowers the apoptotic threshold in a subset of patient-derived glioblastoma (GBM) cells. Mechanistic studies revealed that after attenuated glucose consumption, Bcl-xL blocks cytoplasmic p53 from triggering intrinsic apoptosis. Consequently, targeting of EGFR-driven glucose metabolism in combination with pharmacological stabilization of p53 with the brain-penetrant small molecule idasanutlin resulted in synthetic lethality in orthotopic glioblastoma xenograft models. Notably, neither the degree of EGFR-signaling inhibition nor genetic analysis of EGFR was sufficient to predict sensitivity to this therapeutic combination. However, detection of rapid inhibitory effects on [18F]fluorodeoxyglucose uptake, assessed through noninvasive positron emission tomography, was an effective predictive biomarker of response in vivo. Together, these studies identify a crucial link among oncogene signaling, glucose metabolism, and cytoplasmic p53, which may potentially be exploited for combination therapy in GBM and possibly other malignancies.

中文翻译:

细胞质p53将癌基因驱动的葡萄糖代谢与细胞凋亡相结合,是胶质母细胞瘤的治疗靶标。

致癌信号和代谢途径之间的相互干扰可能为癌症的新治疗策略创造机会。在这里我们显示,尽管对EGFR驱动的葡萄糖代谢的急性抑制仅诱导了最小程度的细胞死亡,但它降低了患者衍生的成胶质细胞瘤(GBM)细胞子集中的凋亡阈值。机理研究表明,减少葡萄糖消耗后,Bcl-xL阻止细胞质p53触发内在凋亡。因此,靶向EGFR驱动的葡萄糖代谢与脑穿透性小分子艾达西林对p53的药理稳定相结合,在原位胶质母细胞瘤异种移植模型中导致了合成杀伤力。尤其,EGFR信号抑制的程度或EGFR的遗传分析都不足以预测对该治疗组合的敏感性。但是,对[通过无创正电子发射断层扫描评估的18 F]氟脱氧葡萄糖摄取是体内反应的有效预测生物标志物。总之,这些研究确定了癌基因信号传导,葡萄糖代谢和细胞质p53之间的关键联系,这些联系可能被广泛用于GBM和其他恶性肿瘤的联合治疗。
更新日期:2017-10-11
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