Potent anti-tumor efficacy of palbociclib in treatment-naive H3.3K27M-mutant diffuse intrinsic pontine glioma
Potent anti-tumor efficacy of palbociclib in treatment-naive H3.3K27M-mutant diffuse intrinsic pontine glioma
复制标题
palbociclib 在未经治疗的 H3.3K27M 突变型弥漫性脑桥胶质瘤中具有强大的抗肿瘤功效
DOI：
10.1016/j.ebiom.2019.04.043
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发表时间：
2019
期刊：
影响因子：
11.1
通讯作者：
Xi Qiaoran
中科院分区：
文献类型：
--
作者：
Sun Yu;Sun Ye;Yan Kun;Li Zhuxuan;Xu Cheng;Geng Yibo;Pan Changcun;Chen Xin;Zhang Liwei;Xi Qiaoran
背景弥漫性内禀脑桥胶质瘤（DIPG）是一种罕见且致命的儿童脑癌，无法治愈。寻找治疗策略仍然是DIPG研究的主要挑战。先前的研究表明，G1/S细胞周期检查点的失调在DIPG中很常见，这种失调在H3.3K27 M突变亚组中更为丰富。在这里，我们评估了palbociclib （CDK4/6的特异性和细胞抑制剂）对高级别H3.3-K27 m突变体DIPGsin体外抗肿瘤的潜在疗效。方法从treatment-naïve标本中建立患者源性细胞系。所有系均有H3.3K27 M突变。我们使用了一系列生物体外检测来评估帕博西尼对dipg生长的影响。帕博西尼对三种独立DIPG异性异种移植模型的体内活性也进行了测定。发现G1/S细胞周期检查点的失调在这些dipg中富集。然后，我们发现cdk4或cdk6的缺失抑制了DIPG细胞的生长并阻断了G1/S转变。此外，帕博西尼能有效抑制DIPG体外生长。转录组分析显示palbociclib不仅阻断G1/S转变，还阻断其他致癌靶点，如MYC。最后，palbociclib在体内对DIPG异性异种移植物的活性进行了测试，以证明其阻断肿瘤生长的高效率。我们的研究结果表明帕博西尼可能是H3.3K27 M突变treatment-naïve DIPG的治疗策略。资助北京市医院管理局临床医学发展专项资金支持、北京市自然科学基金、中国科学技术部、国家自然科学基金。
BackgroundDiffuse intrinsic pontine glioma (DIPG) is a rare and fatal pediatric brain cancer without cure. Seeking therapeutic strategies is still a major challenge in DIPG research. Previous study has shown that dysregulation of G1/S cell cycle checkpoint was common in DIPG and this dysregulation is even more enriched in the H3.3K27 M mutant subgroup. Here we assess potential anti-tumor efficacy of palbociclib, a specific and cytostatic inhibitor of CDK4/6, on high grade H3.3-K27 M-mutant DIPGsin vitroandin vivo.MethodsWe established patient-derived cell lines from treatment-naïve specimens. All the lines have H3.3K27 M mutation. We used a range of biologicalin vitroassays to assess the effect of palbociclib on growth of DIPGs. Palbociclib activity was also assayedin vivoagainst three independent DIPG orthotropic xenografts model.FindingsDysregulation of G1/S cell cycle checkpoint is enriched in these DIPGs. Then, we showed that depletion ofCDK4orCDK6inhibits DIPG cells growth and blocks G1/S transition. Furthermore, palbociclib effectively repressed DIPG growthin vitro. Transcriptome analysis showed that palbociclib not only blocks G1/S transition, it also blocks other oncogenic targets such as MYC. Finally, palbociclib activity was assayedin vivoagainst DIPG orthotropic xenografts to demonstrate the high efficiency of blocking tumor growth.InterpretationOur findings thus revealed that palbociclib could be the therapeutic strategy for treatment-naïve DIPG with H3.3K27 M mutation.FundBeijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support, Beijing Municipal Natural Science Foundation, Ministry of Science and Technology of China, and National Natural Science Foundation of China.