TP53 disruptive mutations lead to head and neck cancer treatment failure through inhibition of radiation-induced senescence.
TP53 disruptive mutations lead to head and neck cancer treatment failure through inhibition of radiation-induced senescence.
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DOI：
10.1158/1078-0432.ccr-11-2260
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发表时间：
2012-01-01
期刊：
影响因子：
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通讯作者：
Myers JN
中科院分区：
文献类型：
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作者：
Skinner HD;Sandulache VC;Ow TJ;Meyn RE;Yordy JS;Beadle BM;Fitzgerald AL;Giri U;Ang KK;Myers JN
头颈鳞状细胞癌 (HNSCC) 患者的死亡率主要是由肿瘤细胞放射抗性导致局部区域复发 (LRR) 驱动的。在本研究中，我们使用 TP53 突变分类（破坏性与非破坏性）并检查对临床结果和放射敏感性的影响。收集了 74 名接受手术和术后放疗的 HNSCC 患者和 38 个 HNSCC 细胞系；对于每一个，TP53 都进行了测序，并使用克隆实验测量了体外放射抗性。使用 shRNA 抑制 p53 蛋白表达，并使用逆转录病毒过表达。进行了辐射诱导的细胞凋亡、有丝分裂细胞死亡、衰老和 ROS 测定。使用原位异种移植模型在体外和体内检查了药物二甲双胍对克服突变型 p53 相关辐射抗性的影响。突变 TP53 单独不能预测 LRR；然而，破坏性 TP53 突变强烈预测 LRR (p=0.03)。具有破坏性突变的细胞系具有显着更高的放射抗性（p<0.05）。通过 SA-β-gal 染色、p21 表达和活性氧 (ROS) 释放来测量，破坏性 TP53 突变的表达显着减少了辐射诱导的衰老。线粒体药物二甲双胍在存在破坏性 TP53 突变的情况下增强了辐射的影响，部分是通过衰老来实现的。对我们的患者队列的检查表明，服用二甲双胍的患者的 LRR 降低。 HNSCC 肿瘤中的破坏性 TP53 突变可预测 LRR，这是由于通过抑制衰老而增加了放射抗性。二甲双胍可以作为具有破坏性 TP53 的 HNSCC 的放射增敏剂，预示着个体化 HNSCC 治疗的可能性。
Mortality of patients with head and neck squamous cell carcinoma (HNSCC) is primarily driven by tumor cell radioresistance leading to locoregional recurrence (LRR). In this study, we use a classification of TP53 mutation (disruptive vs. nondisruptive) and examine impact on clinical outcomes and radiation sensitivity. Seventy-four patients with HNSCC treated with surgery and postoperative radiation and 38 HNSCC cell lines were assembled; for each, TP53 was sequenced and in vitro radioresistance measured using clonogenic assays. p53 protein expression was inhibited using shRNA and over-expressed using a retrovirus. Radiation-induced apoptosis, mitotic cell death, senescence, and ROS assays were performed. The effect of the drug metformin on overcoming mutant p53-associated radiation resistance was examined in vitro as well as in vivo, using an orthotopic xenograft model. Mutant TP53 alone was not predictive of LRR; however, disruptive TP53 mutation strongly predicted LRR (p=0.03). Cell lines with disruptive mutations were significantly more radioresistant (p<0.05). Expression of disruptive TP53 mutations significantly decreased radiation-induced senescence, as measured by SA-beta-gal staining, p21 expression, and release of reactive oxygen species (ROS). The mitochondrial agent metformin potentiated the effects of radiation in the presence of a disruptive TP53 mutation partially via senescence. Examination of our patient cohort showed that LRR was decreased in patients taking metformin. Disruptive TP53 mutations in HNSCC tumors predicts for LRR, due to increased radioresistance via the inhibition of senescence. Metformin can serve as a radiosensitizer for HNSCC with disruptive TP53, presaging the possibility of personalizing HNSCC treatment.