Combined ATR and DNA-PK Inhibition Radiosensitizes Tumor Cells Independently of Their p53 Status.
Combined ATR and DNA-PK Inhibition Radiosensitizes Tumor Cells Independently of Their p53 Status.
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DOI：
10.3389/fonc.2018.00245
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发表时间：
2018
影响因子：
4.7
通讯作者：
Harrington KJ
中科院分区：
文献类型：
--
作者：
Hafsi H;Dillon MT;Barker HE;Kyula JN;Schick U;Paget JT;Smith HG;Pedersen M;McLaughlin M;Harrington KJ
头颈部鳞状细胞癌(HNSCC)是癌症死亡的重要原因。以顺铂为基础的放化疗是治疗局部晚期疾病的标准疗法。ATR和DNA-PK抑制(DNA-PKI)正被积极地研究在临床试验中，临床前数据支持临床翻译作为放射增敏剂。在这里，我们假设靶向ATR和DNA-PK的小分子抑制剂将增加HNSCC细胞系的放射增敏。对集落存活数据进行Bliss独立性分析，评价放射增敏作用。ATR的抑制逆转了辐射-DNA-PKI的G2/M期阻滞，观察到了强烈的细胞周期扰动效应。通过Sub-G1DNA群体检测联合用药组细胞凋亡率增加。DNA-PKI增加了辐射诱导的RAD51和伽马-H_2AX焦点，ATR抑制降低了两者的水平。有丝分裂异常转运后核碎裂的急剧增加似乎是辐射和双重ATR/DNA-PKI导致存活率下降的主要原因。DNA-PK和ATR的双重抑制代表了一种与放射治疗相结合的新方法，其疗效似乎与P53状态无关。由于毒性方面的考虑，在今后对单一或双重放射增敏方法的任何翻译中都必须进行仔细的评估。正在进行的ATR抑制剂AZD6738加放射的临床试验，以及AZD6738和PARP抑制剂olaparib的表型相似的组合，可能是确定这些组合的毒性图谱的关键。
Head and neck squamous cell carcinoma (HNSCC) is a significant cause of cancer deaths. Cisplatin-based chemoradiotherapy is a standard of care for locally advanced disease. ATR and DNA-PK inhibition (DNA-PKi) are actively being investigated in clinical trials with preclinical data supporting clinical translation as radiosensitizers. Here, we hypothesized that targeting both ATR and DNA-PK with small molecule inhibitors would increase radiosensitization of HNSCC cell lines. Radiosensitization was assessed by Bliss independence analysis of colony survival data. Strong cell cycle perturbing effects were observed with ATR inhibition reversing the G2/M arrest observed for radiation-DNA-PKi. Increased apoptosis in combination groups was measured by Sub-G1 DNA populations. DNA-PKi increased radiation-induced RAD51 and gamma-H2Ax foci, with the addition of ATR inhibition reducing levels of both. A sharp increase in nuclear fragmentation after aberrant mitotic transit appears to be the main driver of decreased survival due to irradiation and dual ATR/DNA-PKi. Dual inhibition of DNA-PK and ATR represents a novel approach in combination with radiation, with efficacy appearing to be independent of p53 status. Due to toxicity concerns, careful assessment is necessary in any future translation of single or dual radiosensitization approaches. Ongoing clinical trials into the ATR inhibitor AZD6738 plus radiation, and the phenotypically similar combination of AZD6738 and the PARP inhibitor olaparib, are likely to be key in ascertaining the toxicity profile of such combinations.
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影响因子：
19
作者：
Ceccaldi R;Rondinelli B;D'Andrea AD
通讯作者：
D'Andrea AD
影响因子：
16
作者：
Buisson R;Boisvert JL;Benes CH;Zou L
通讯作者：
Zou L
DNA-PKcs 的差异磷酸化调节非同源末端连接过程中末端加工和末端连接之间的相互作用。
影响因子：
16
作者：
Jiang W;Crowe JL;Liu X;Nakajima S;Wang Y;Li C;Lee BJ;Dubois RL;Liu C;Yu X;Lan L;Zha S
通讯作者：
Zha S
DOI：
10.3109/10409238.2011.575764
发表时间：
2011-08
影响因子：
6.5
作者：
Deckbar D;Jeggo PA;Löbrich M
通讯作者：
Löbrich M
影响因子：
5.7
作者：
Dillon MT;Barker HE;Pedersen M;Hafsi H;Bhide SA;Newbold KL;Nutting CM;McLaughlin M;Harrington KJ
通讯作者：
Harrington KJ