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Abstract There is a noted trend in the identification and subsequent approval of rational drug combinations to treat various diseases, particularly cancer. When applied in a clinical setting, synergistic combinations can have significant benefits including improved patient response and avoiding or overcoming drug resistance. Although multiple strategies have been successfully implemented to identify rational drug combinations, extensive validation is initially required to confirm a combination as synergistic. The existence and growing use of web-based repositories containing comprehensive drug combination data is a key resource and can be a valuable starting point for identifying synergistic combinations. However, are synergistic combinations from these datasets expected or rational and can they be validated experimentally? By mining available drug combinations from the DrugCombo database, we wanted to identify unusual drug combinations reported as synergistic and experimentally validate these with dose-response assays. In addition, we set out to establish if cytokines could be used as an inhibition biomarker to easily assess synergy. We found multiple unexpected synergies including a predicted synergy between the JAK1/2 inhibitor Ruxolitinib with Maraviroc, a CCR5 antagonist, or Levetiracetam, an SV2A binding anti-epileptic reported in the lymphoma cell line, L-1236. Experimentally, these predicted synergies could not be validated. In the context of synergistic drug combinations, this work shows that experimental validation is crucial, particularly for combinations with uncertain biological mechanisms. Citation Format: Rainer Grant, Marco Pinheiro, Rachel Weller Roska, Robert Felix. Identification and validation of unusual drug combinations identified from combination databases abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 943.
Grant et al. (Fri,) studied this question.