药物协同作用是一种吸引人的抗癌策略。然而，随着超过5000种已批准的药物和临床研究中的化合物，鉴定协同治疗方法仍面临重大挑战。高通量筛选结合目标分离和功能基因组学的方法被用于揭示神经胶质母细胞瘤中可靶向的易感性。通过RNA干扰、转录组学和免疫组织化学对患者样本中的顶级基因袭击的作用进行了研究。使用包含88种化合物的自定义库与已确定的神经胶质母细胞瘤易感性的六种抑制剂进行药物组合筛选，以揭示药物协同作用。神经胶质母细胞瘤的3D球体、体外器官和同种异源的正交移植小鼠模型被用于验证协同治疗。在神经胶质母细胞瘤中鉴定了九个可靶向的易感性，并验证了顶级基因袭击RRM1作为独立的预后因子。通过528种已测试的成对药物组合中，CHK1/MEK和AURKA/BET抑制剂的关联性被确定为最有效的，并且在3D球体模型中验证了它们的功效。AURKA/BET双重抑制的高度协同作用在体外和体内神经胶质母细胞瘤模型中得到了确认，并且没有检测到毒性。我们的研究为AURKA/BET抑制剂组合在神经胶质母细胞瘤中的功效提供了强有力的临床前证据，并为这一未满足的医疗需求开辟了新的治疗途径。此外，我们建立了通过利用药物多药性来揭示可用于治疗癌症易感性和快速确定抗耐药癌症的药物协同组合的逐步方法的概念证明。本研究得到了机构资助和慈善基金的支持。版权所有©2023The Author(s)。出版者Elsevier B.V.保留所有权利。

Pharmacological synergisms are an attractive anticancer strategy. However, with more than 5000 approved-drugs and compounds in clinical development, identifying synergistic treatments represents a major challenge.High-throughput screening was combined with target deconvolution and functional genomics to reveal targetable vulnerabilities in glioblastoma. The role of the top gene hit was investigated by RNA interference, transcriptomics and immunohistochemistry in glioblastoma patient samples. Drug combination screen using a custom-made library of 88 compounds in association with six inhibitors of the identified glioblastoma vulnerabilities was performed to unveil pharmacological synergisms. Glioblastoma 3D spheroid, organotypic ex vivo and syngeneic orthotopic mouse models were used to validate synergistic treatments.Nine targetable vulnerabilities were identified in glioblastoma and the top gene hit RRM1 was validated as an independent prognostic factor. The associations of CHK1/MEK and AURKA/BET inhibitors were identified as the most potent amongst 528 tested pairwise drug combinations and their efficacy was validated in 3D spheroid models. The high synergism of AURKA/BET dual inhibition was confirmed in ex vivo and in vivo glioblastoma models, without detectable toxicity.Our work provides strong pre-clinical evidence of the efficacy of AURKA/BET inhibitor combination in glioblastoma and opens new therapeutic avenues for this unmet medical need. Besides, we established the proof-of-concept of a stepwise approach aiming at exploiting drug poly-pharmacology to unveil druggable cancer vulnerabilities and to fast-track the identification of synergistic combinations against refractory cancers.This study was funded by institutional grants and charities.Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.