Menden, Michael PWang, DennisMason, Mike JSzalai, BenceBulusu, Krishna CGuan, YuanfangYu, ThomasKang, JaewooJeon, MinjiWolfinger, RussNguyen, TinZaslavskiy, MikhailAstraZeneca-Sanger Drug Combination DREAM ConsortiumJang, In SockGhazoui, ZaraAhsen, Mehmet ErenVogel, RobertNeto, Elias ChaibubNorman, TheaTang, Eric K YGarnett, Mathew JVeroli, Giovanni Y DiFawell, StephenStolovitzky, GustavoGuinney, JustinDry, Jonathan RSaez-Rodriguez, Julio2025-01-072025-01-072019-06-17https://hdl.handle.net/10668/25009The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca's large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/ADAM17 ProteinAntineoplastic Combined Chemotherapy ProtocolsBenchmarkingBiomarkers, TumorCell Line, TumorComputational BiologyDatasets as TopicDrug AntagonismDrug Resistance, NeoplasmDrug SynergismGenomicsHumansMolecular Targeted TherapyMutationNeoplasmsPharmacogeneticsPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsTreatment Outcomeresearch article31209238open access10.1038/s41467-019-09799-22041-1723PMC6572829https://www.nature.com/articles/s41467-019-09799-2.pdfhttps://pmc.ncbi.nlm.nih.gov/articles/PMC6572829/pdf