CDK4/6 inhibition is more active against the glioblastoma proneural subtype.
CDK4/6 inhibition is more active against the glioblastoma proneural subtype.
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DOI：
10.18632/oncotarget.19429
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发表时间：
2017-08-15
期刊：
影响因子：
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通讯作者：
Purow B
中科院分区：
文献类型：
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作者：
Li M;Xiao A;Floyd D;Olmez I;Lee J;Godlewski J;Bronisz A;Bhat KPL;Sulman EP;Nakano I;Purow B
胶质母细胞瘤（GBM）是最常见和致命的脑肿瘤。基因表达谱将 GBM 分为不同的亚型，包括原神经型、间充质型和经典型，识别这些亚型的治疗脆弱性是当务之急。我们利用癌症基因组图谱 (TCGA) 数据，特别是 microRNA 表达的数据，来寻找 GBM 中可药物化的核心途径。 E2F1调节的miR-17〜92簇及其类似物显示在原神经GBM和GSC系中高表达，表明E2F细胞周期途径可能是原神经GBM的关键驱动因素。一致地，与其他亚型相比，palbociclib 抑制 CDK4/6 优先抑制大多数原神经 GSC 的体外细胞增殖。 Palbociclib 治疗显着延长了已建立原神经 GSC 系颅内异种移植物的小鼠的生存期。我们发现，大多数这些敏感的 PN GSC 表达较高水平的 CDK6 并具有完整的 Rb1，而 CDK4 过表达和 Rb1 缺失的两个 GSC 系对哌柏西利高度耐药。重要的是，palbociclib 治疗原神经 GSC 上调间充质相关标记并下调原神经相关标记，表明 CDK4/6 抑制诱导原神经 - 间质转化，并强调 E2F 细胞周期途径在原神经亚型中的增强作用。最后，palbociclib 与 N,N-二乙氨基苯甲醛（一种间充质驱动程序 ALDH1A3 的抑制剂）组合，对原神经 GSC 增殖表现出强烈的协同抑制作用。综上所述，我们的结果表明，原神经 GBM 对 CDK4/6 抑制的脆弱性增加，并且原神经亚型在 Palbociclib 治疗后经历动态重编程，这表明需要联合治疗策略。
Glioblastoma (GBM) is the most common and lethal brain tumor. Gene expression profiling has classified GBM into distinct subtypes, including proneural, mesenchymal, and classical, and identifying therapeutic vulnerabilities of these subtypes is an extremely high priority. We leveraged The Cancer Genome Atlas (TCGA) data, in particular for microRNA expression, to seek druggable core pathways in GBM. The E2F1-regulated miR-17˜92 cluster and its analogs are shown to be highly expressed in proneural GBM and in GSC lines, suggesting the E2F cell cycle pathway might be a key driver in proneural GBM. Consistently, CDK4/6 inhibition with palbociclib preferentially inhibited cell proliferation in vitro in a majority of proneural GSCs versus those of other subtypes. Palbociclib treatment significantly prolonged survival of mice with established intracranial xenografts of a proneural GSC line. We show that most of these sensitive PN GSCs expressed higher levels of CDK6 and had intact Rb1, while two GSC lines with CDK4 overexpression and null Rb1 were highly resistant to palbociclib. Importantly, palbociclib treatment of proneural GSCs upregulated mesenchymal-associated markers and downregulated proneural-associated markers, suggesting that CDK4/6 inhibition induced proneural-mesenchymal transition and underscoring the enhanced role of the E2F cell cycle pathway in the proneural subtype. Lastly, the combination of palbociclib and N,N-diethylaminobenzaldehyde, an inhibitor of the mesenchymal driver ALDH1A3, showed strong synergistic inhibitory effects against proneural GSC proliferation. Taken together, our results reveal that proneural GBM has increased vulnerability to CDK4/6 inhibition, and the proneural subtype undergoes dynamic reprogramming upon palbociclib treatment—suggesting the need for a combination therapeutic strategy.