GEOTranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE279738GEOGSEfalseA novel combination of CDK4/6 and PI3K inhibitors exhibits highly synergistic activity and translational potential in Ewing sarcoma.Ewing sarcoma is a highly aggressive solid tumor malignancy and the second most common bone cancer in children. Ewing sarcoma is driven primarily by EWS-FLI, a fusion oncoprotein that has been notoriously difficult to target with traditional pharmacological agents. Compared to adult cancers, pediatric malignancies are rarely driven by readily druggable oncogenic targets and there are few incentives for developing drugs for challenging targets restricted to relatively uncommon cancer types. In addition, the effectiveness of single-agent therapies for cancer treatment is often limited. Furthermore, there are numerous examples of promising combinations of preclinical small molecules that are never tested in pediatric clinical trials because agents fail to reach the market due to limited efficacy for common adult cancers. Therefore, the identification of novel effective candidate treatment combinations comprised of anti-cancer drugs already commercially available would likely expedite the development of clinical trials for patients with pediatric cancers. To identify candidate treatment combinations for Ewing sarcoma, we performed a high-throughput drug screening with 180 combinations of tyrosine kinase inhibitors, cell cycle inhibitors, and chemotherapies, that were largely FDA approved or in late stages of clinical development. The results of the screen revealed that a CDK4/6 inhibitor ribociclib combined with a PI3K inhibitor copanlisib exhibited strong synergistic anti-Ewing sarcoma activity. We showed that this combination induced apoptosis and cell cycle arrest more effectively than either agent alone in vitro and impaired tumor proliferation and prolonged survival in vivo compared to mice treated with vehicle or single-agent therapy. Our findings identified a new candidate therapeutic option for Ewing sarcoma patients using FDA-approved drugs and provide a resource of additional potential synergistic combinations for future validation.2026/05/31GSE279738GSM8579448GSM8579449GSM8579462GSM8579440GSM8579441GSM8579442GSM8579443GSM8579444GSM8579445GSM8579446GSM8579447GSM8579460GSM8579461GSM8579459GSM8579437GSM8579438GSM8579439GSM8579451GSM8579452GSM8579453GSM8579431GSM8579454GSM8579432GSM8579433GSM8579455GSM8579456GSM8579434GSM8579457GSM8579435GSM8579436GSM8579458GSM857945024676279738Homo sapiens