Unbiased combination screening on repurposed drugs reveals synergistic potential of copanlisib and cerivastatin against chemoresistant high-grade serous ovarian cancer
Notice bibliographique
Résumé
INTRODUCTION: High-grade serous ovarian cancers (HGSOCs) are challenging to treat and often resistant to therapy. Despite ongoing therapeutic progress, relapse and poor outcomes remain common among both newly diagnosed and recurrent cases. Systematic high-throughput screening of clinically approved compounds holds significant promise for uncovering novel therapeutic responses and developing new treatment strategies for this disease. METHODS: A panel of drugs were screened for cytotoxicity in five HGSOC cell lines, with drug efficacy quantified using the drug sensitivity score (DSS). All pairwise combinations of 384 low-cytotoxic drugs were screened by grouping 10 compounds in each well. The potent 10-compound combinations were deconvoluted into 2-drug pairings for secondary screening and ranked by the Bliss independent model and the Loewe additive model. Promising drug responses were further characterised in 3D spheroid cultures and patient ascites-derived cells (PADCs). The mechanism of action of the drugs was investigated by Western blot analysis. RESULTS: The DSS profile of drug responses provided a more robust clustering of 5 HGSOC cell lines according to their chemosensitivity responses compared to gene expression analysis of chemoresistance markers. Furthermore, chemoresistant HGSOC cell lines exhibited limited efficacy to single-agent treatments and generally demonstrated resistance to most anti-cancer agents. However, combination screens identified several novel drug pairings that were cytotoxic to chemoresistant HGSOC cells. Drug combinations involving traditional anticancer agents showed superior synergy and toxicity in chemosensitive cell lines, while all cell lines demonstrated good sensitivity to PI3K and HMG-CoA reductase inhibitors at sub-maximal clinically relevant concentrations, with the greatest sensitivity observed in chemoresistant cells. The combination of PI3K and HMG-CoA reductase inhibition significantly reduced the viability and growth of HGSOC spheroids. PADCs exhibited intrinsic sensitivity to HMG-CoA inhibition, while the combination with PI3K inhibition facilitated further dose reductions. Mechanistic studies revealed that the HMG-CoA inhibitor increased phospho-Akt levels in chemoresistant cell lines, sensitising them to PI3K inhibition. CONCLUSION: This study demonstrates the application of multiplex drug combination screening to identify effective synergistic therapies. Co-targeting PI3-kinase and HMG-CoA reductase could be repurposed as a potent combination to treat chemoresistant HGSOC.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,002 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».