Combination of BMI1 and MAPK/ERK inhibitors is effective in medulloblastoma.
Combination of BMI1 and MAPK/ERK inhibitors is effective in medulloblastoma.
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DOI：
10.1093/neuonc/noac052
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发表时间：
2022-08-01
期刊：
影响因子：
15.9
通讯作者：
中科院分区：
文献类型：
--
作者：
表观遗传变化在髓母细胞瘤（MB）（最常见的恶性儿童脑肿瘤）的发病机制中发挥着关键作用。我们探索了 BMI1High;CHD7Low MB 细胞和临床前异种移植模型中 BMI1 和 MAPK/ERK 抑制的治疗潜力。我们确定了 BMI1High;CHD7Low MB 细胞对 BMI1 和 MAPK/ERK 抑制剂联合治疗的协同脆弱性。从机制上讲，BMI1 与 MAPK 调节基因的 CHD7 依赖性结合支撑了 CHD7-BMI1-MAPK 调节轴，负责抑制剂的体外和临床前小鼠模型中的抗肿瘤作用。在 BMI1High;CHD7Low G4 MB 患者中发现 ERK1 和 ERK2 磷酸化活性增加，这提高了他们接受类似治疗的可能性。对 BMI1High;CHD7Low MB 中 CHD7-BMI1-MAPK 调节轴的分子剖析将这一特征确定为预测 MAPK 功能激活的代理，可以在临床前模型中有效用药，并为进一步探索 G4 MB 患者中 BMI1 和 MAPK 联合靶向治疗铺平道路。
Epigenetic changes play a key role in the pathogenesis of medulloblastoma (MB), the most common malignant pediatric brain tumor. We explore the therapeutic potential of BMI1 and MAPK/ERK inhibition in BMI1High;CHD7Low MB cells and in a preclinical xenograft model. We identify a synergistic vulnerability of BMI1High;CHD7Low MB cells to a combination treatment with BMI1 and MAPK/ERK inhibitors. Mechanistically, CHD7-dependent binding of BMI1 to MAPK-regulated genes underpins the CHD7-BMI1-MAPK regulatory axis responsible of the antitumour effect of the inhibitors in vitro and in a preclinical mouse model. Increased ERK1 and ERK2 phosphorylation activity is found in BMI1High;CHD7Low G4 MB patients, raising the possibility that they could be amenable to a similar therapy. The molecular dissection of the CHD7-BMI1-MAPK regulatory axis in BMI1High;CHD7Low MB identifies this signature as a proxy to predict MAPK functional activation, which can be effectively drugged in preclinical models, and paves the way for further exploration of combined BMI1 and MAPK targeting in G4 MB patients.
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影响因子：
16.6
作者：
Badodi S;Pomella N;Zhang X;Rosser G;Whittingham J;Niklison-Chirou MV;Lim YM;Brandner S;Morrison G;Pollard SM;Bennett CD;Clifford SC;Peet A;Basson MA;Marino S
通讯作者：
Marino S
影响因子：
50.3
作者：
Gargiulo, Gaetano;Cesaroni, Matteo;van Lohuizen, Maarten
通讯作者：
van Lohuizen, Maarten
影响因子：
8.8
作者：
Badodi S;Dubuc A;Zhang X;Rosser G;Da Cunha Jaeger M;Kameda-Smith MM;Morrissy AS;Guilhamon P;Suetterlin P;Li XN;Guglielmi L;Merve A;Farooq H;Lupien M;Singh SK;Basson MA;Taylor MD;Marino S
通讯作者：
Marino S
影响因子：
9
作者：
Frisira, Eleni;Rashid, Fatima;Niklison-Chirou, Maria Victoria
通讯作者：
Niklison-Chirou, Maria Victoria
影响因子：
8
作者：
Bakhshinyan, David;Venugopal, Chitra;Singh, Sheila K.
通讯作者：
Singh, Sheila K.