Glioblastoma (GBM) is a highly aggressive and lethal brain cancer type. PI3K and MAPK inhibitors have been studied preclinically in GBM as monotherapy, but not in combination with radiotherapy, which is a key component of the current standard treatment of GBM. In our study, GBM cell lines and patient representative primary cultures were grown as multicellular spheroids. Spheroids were treated with a panel of small-molecule drugs including MK2206, RAD001, BEZ235, MLN0128, and MEK162, alone and in combination with irradiation. Following treatment, spheroid growth parameters (growth rate, volume reduction, and time to regrow), cell-cycle distribution and expression of key target proteins were evaluated. In vivo, the effect of irradiation (3 × 2 Gy) without or with MEK162 (50 mg/kg) was studied in orthotopic GBM8 brain tumor xenografts with endpoints tumor growth and animal survival. The MAPK-targeting agent MEK162 was found to enhance the effect of irradiation as demonstrated by growth inhibition of spheroids. MEK162 downregulated and dephosphorylated the cell-cycle checkpoint proteins CDK1/CDK2/WEE1 and DNA damage response proteins p-ATM/p-CHK2. When combined with radiation, this led to a prolonged DNA damage signal. In vivo data on tumor-bearing animals demonstrated a significantly reduced growth rate, increased growth delay, and prolonged survival time. In addition, RNA expression of responsive cell cultures correlated to mesenchymal stratification of patient expression data. In conclusion, the MAPK inhibitor MEK162 was identified as a radiosensitizer in GBM spheroids in vitro and in orthotopic GBM xenografts in vivo. The data are supportive for implementation of this targeted agent in an early-phase clinical study in GBM patients. Mol Cancer Ther; 17(2); 347–54. ©2017 AACR. See all articles in this MCT Focus section, “Developmental Therapeutics in Radiation Oncology.”

中文翻译：

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鉴定 MEK162 作为治疗胶质母细胞瘤的放射增敏剂

胶质母细胞瘤 (GBM) 是一种高度侵袭性和致命的脑癌类型。PI3K 和 MAPK 抑制剂已在 GBM 中作为单一疗法进行了临床前研究，但未与放疗联合进行研究，放疗是目前 GBM 标准治疗的关键组成部分。在我们的研究中，GBM 细胞系和患者代表性原代培养物生长为多细胞球体。球体用一组小分子药物治疗，包括 MK2206、RAD001、BEZ235、MLN0128 和 MEK162，单独和与辐射组合。治疗后，对球体生长参数（生长速率、体积减少和再生时间）、细胞周期分布和关键靶蛋白的表达进行了评估。体内，在原位 GBM8 脑肿瘤异种移植物中研究了没有或有 MEK162 (50 mg/kg) 的辐射 (3 × 2 Gy) 的影响，终点是肿瘤生长和动物存活。发现 MAPK 靶向剂 MEK162 可增强辐照效果，如球体的生长抑制所证明的那样。MEK162 下调和去磷酸化细胞周期检查点蛋白 CDK1/CDK2/WEE1 和 DNA 损伤反应蛋白 p-ATM/p-CHK2。当与辐射相结合时，这会导致 DNA 损伤信号延长。荷瘤动物的体内数据表明生长速度显着降低，生长延迟增加，存活时间延长。此外，响应细胞培养物的 RNA 表达与患者表达数据的间充质分层相关。综上所述，MAPK 抑制剂 MEK162 被鉴定为体外 GBM 球体和体内原位 GBM 异种移植物中的放射增敏剂。这些数据支持在 GBM 患者的早期临床研究中实施这种靶向药物。摩尔癌症治疗; 17(2); 347-54。©2017 AACR。请参阅此 MCT 焦点部分中的所有文章，“放射肿瘤学中的发育疗法”。