Combination drug screen targeting glioblastoma core vulnerabilities reveals pharmacological synergisms.

Autor:	Ariey-Bonnet J; Aix Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), Marseille, France., Berges R; Aix Marseille Université, CNRS, UMR 7051, INP, Inst Neurophysiopathol, Marseille, France., Montero MP; Aix Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), Marseille, France., Mouysset B; Aix Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), Marseille, France., Piris P; Aix Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), Marseille, France., Muller K; Aix Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), Marseille, France., Pinna G; Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, University Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette F-91198, France., Failes TW; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW 2052, Australia; ACRF Drug Discovery Centre for Childhood Cancer, Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW 2052, Australia., Arndt GM; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW 2052, Australia; ACRF Drug Discovery Centre for Childhood Cancer, Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW 2052, Australia., Morando P; Aix Marseille Université, CNRS, UMR 7051, INP, Inst Neurophysiopathol, Marseille, France., Baeza-Kallee N; Aix Marseille Université, CNRS, UMR 7051, INP, Inst Neurophysiopathol, Marseille, France., Colin C; Aix Marseille Université, CNRS, UMR 7051, INP, Inst Neurophysiopathol, Marseille, France., Chinot O; Aix-Marseille University, Assistance Publique-Hopitaux de Marseille, Centre Hospitalo-Universitaire Timone, Service de Neuro-Oncologie, Marseille, France., Braguer D; Aix Marseille Université, CNRS, UMR 7051, INP, Inst Neurophysiopathol, Marseille, France., Morelli X; Aix Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), Marseille, France., André N; Aix Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), Marseille, France; Pediatric Oncology and Hematology Department, Hôpital pour Enfant de La Timone, AP-HM, Marseille, France; Metronomics Global Health Initiative, Marseille 13385, France., Carré M; Aix Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), Marseille, France., Tabouret E; Aix Marseille Université, CNRS, UMR 7051, INP, Inst Neurophysiopathol, Marseille, France; Aix-Marseille University, Assistance Publique-Hopitaux de Marseille, Centre Hospitalo-Universitaire Timone, Service de Neuro-Oncologie, Marseille, France., Figarella-Branger D; Aix Marseille Université, CNRS, UMR 7051, INP, Inst Neurophysiopathol, Marseille, France., Le Grand M; Aix Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), Marseille, France. Electronic address: marion.le-grand@inserm.fr., Pasquier E; Aix Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), Marseille, France; Metronomics Global Health Initiative, Marseille 13385, France. Electronic address: eddy.pasquier@inserm.fr.
Jazyk:	angličtina
Zdroj:	EBioMedicine [EBioMedicine] 2023 Sep; Vol. 95, pp. 104752. Date of Electronic Publication: 2023 Aug 10.
DOI:	10.1016/j.ebiom.2023.104752
Abstrakt:	Background: 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. Methods: 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. Findings: 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. Interpretation: 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. Funding: This study was funded by institutional grants and charities. Competing Interests: Declaration of interests The authors have declared no conflict of interest. (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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