在目前的治疗方式下，胶质母细胞瘤（GBM）难以有效治疗，同时治疗的副作用会导致神经毒性和认知损伤。本研究假设抑制CDK7或CDK9可以有效对抗GBM，并减少神经毒性。我们检测了CDK7抑制剂THZ1和多个CDK9抑制剂（SNS032、AZD4573、NVP2和JSH150）对GBM细胞系、耐替莫唑胺（TMZ）和敏感原发肿瘤细胞以及胶质瘤干细胞（GSCs）的影响。通过免疫印迹、免疫荧光、多光谱成像和RT-PCR技术评估了生化变化。通过原位和皮下移植模型评估了体内效力。 在低纳摩尔浓度下，CDK7和CDK9抑制剂抑制了对替莫唑胺敏感和耐药的GBM细胞和GSCs的存活率，体内细胞毒性效应有限。这些抑制剂撤消了RNA Pol II和p70S6K的磷酸化以及新生蛋白质的合成。此外，GSCs的自我更新显著降低，并伴随着Sox2和Sox9水平的减少。TCGA数据分析显示，在GBM中CDK7、CDK9、SOX2、SOX9和RPS6KB1的表达增加；支持这一点的是，对一份TMA的多光谱成像显示，相对于正常大脑，GBM中的CDK9、Sox2、Sox9、磷酸化S6和磷酸化p70S6K水平升高。RNA-Seq结果表明，这些抑制剂能够抑制肿瘤促进基因，同时诱导肿瘤抑制基因的表达。此外，在皮下和原位GBM肿瘤移植模型上进行的研究显示，CDK9抑制剂的给药显著抑制了体内的肿瘤生长。 我们的研究结果表明，CDK7和CDK9靶向治疗可能对TMZ敏感和耐药的GBM有效。© 作者（2023）。由牛津大学出版社代表神经肿瘤学会出版。保留所有权利。有关权限，请发送电子邮件至：journals.permissions@oup.com。

Glioblastoma (GBM) is refractory to current treatment modalities while side effects of treatments result in neurotoxicity and cognitive impairment. Here we test the hypothesis that inhibiting CDK7 or CDK9 would effectively combat GBM with reduced neurotoxicity.We examined the effect of a CDK7 inhibitor, THZ1, and multiple CDK9 inhibitors (SNS032, AZD4573, NVP2, and JSH150) on GBM cell lines, patient-derived temozolomide (TMZ)-resistant and responsive primary tumor cells and glioma stem cells (GSCs). Biochemical changes were assessed by western blotting, immunofluorescence, multispectral imaging, and RT-PCR. In vivo efficacy was assessed in orthotopic and subcutaneous xenograft models.CDK7 and CDK9 inhibitors suppressed the viability of TMZ-responsive and resistant GBM cells and GSCs at low nanomolar concentrations, with limited cytotoxic effects in vivo. The inhibitors abrogated RNA Pol II and p70S6K phosphorylation and nascent protein synthesis. Furthermore, the self-renewal of GSCs was significantly reduced with a corresponding reduction in Sox2 and Sox9 levels. Analysis of TCGA data showed increased expression of CDK7, CDK9, SOX2, SOX9, and RPS6KB1 in GBM; supporting this, multispectral imaging of a TMA revealed increased levels of CDK9, Sox2, Sox9, phospho-S6 and phospho-p70S6K in GBM compared to normal brains. RNA-Seq results suggested that inhibitors suppressed tumor promoting genes while inducing tumor suppressive genes. Further, the studies conducted on subcutaneous and orthotopic GBM tumor xenograft models showed that administration of CDK9 inhibitors markedly suppressed tumor growth in vivo.Our results suggest that CDK7 and CDK9 targeted-therapies may be effective against TMZ-sensitive and resistant GBM.© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.