Article
Combinatorial drug screening identifies synergistic interactions of Bcl-2 inhibitor Navitoclax with MELK inhibitor OTSSP167 and HDAC inhibitor Panobinostat for the treatment of aggressive meningiomas
Medikamenten-Kombinationsscreening identifiziert synergistische Interaktionen des Bcl-2 Inhibitors Navitoclax mit dem MELK Inhibitor OTSSP167 und HDAC Inhibitor Panobinostat für die Behandlung von aggressiven Meningeomen
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Authors
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Junguo Cao
- Universitätsklinikum Heidelberg, Neurochirurgische Klinik, Heidelberg, Deutschland
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Gerhard Jungwirth
- Universitätsklinikum Heidelberg, Neurochirurgische Klinik, Heidelberg, Deutschland
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Rolf Warta
- Universitätsklinikum Heidelberg, Neurochirurgische Klinik, Heidelberg, Deutschland
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Andreas W. Unterberg
- Universitätsklinikum Heidelberg, Neurochirurgische Klinik, Heidelberg, Deutschland
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Christel Herold-Mende
- Universitätsklinikum Heidelberg, Neurochirurgische Klinik, Heidelberg, Deutschland
| Published: | May 25, 2022 |
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Outline
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Objective: Combinatorial targeted therapy has been suggested as a powerful approach to overcome drug resistance and also might lead to a dose reduction of the single drugs. Based on a previous drug screening in meningioma cell lines, we identified OTSSP167 (MELK inhibitor) and Panobinostat (HDAC inhibitor) as highly effective single agent drugs. To enhance their therapeutic effect, our study aimed at identifying potential synergistic drug combinations in vitro and ex vivo for the treatment of aggressive meningiomas.
Methods: A two-step approach of combinatorial drug screening was performed in two anaplastic meningioma cell lines (NCH93, IOMM-Lee). First, IC30 concentrations of OTSSP167 or Panobinostat were combined with each drug of a custom drug library (n=104) in a single dose (2.5 µM). Drug combinations with an over-additive effect were further evaluated in 8x8 dose-response matrices (DRM), and ZIP synergistic scores were calculated in R. Cell viability was assessed by CellTiter-Glo 2D. Cell cycle analysis, annexin V/PI staining, and Caspase-Glo 3/7 assay were performed on two additional meningioma cell lines. Drug combinations were further validated in patient-derived meningioma organoid 3D models.
Results: Combinatorial drug screening identified five over-additive drug combinations. Validation of these combinations in DRMs revealed robust synergistic interactions of the Bcl-2 inhibitor Navitoclax with OTSSP167 (ZIP synergy score 20.9) and Panobinostat (11.9), which were selected for further functional tests. Combination treatment induced apoptosis as evaluated by cell cycle as an increase of cells in subG1-phase from 0.5%-5.6% to 12.0%-32.6%, and from 0.5%-5.6% to 3.0%-22.5% in four meningioma cell lines compared to monotherapy, respectively (P<0.001). These results were further confirmed by Annexin V/PI staining and caspase 3/7-assay (P<0.001). Treatment of patient-derived meningioma organoids from four patients in DRMs resulted in highly synergistic inhibitory effects of these two combinations (ZIP scores 10.7 to 17.8, P<0.001).
Conclusion: Combinatorial drug screening identified Bcl-2 inhibitor Navitoclax to act synergistic with OTSSP167 or Panobinostat in vitro and in patient-derived meningioma organoids. Further investigation is needed to explore the molecular mechanism of their synergistic effects.
