Validation of Atypical Drug Combinations Identified from Combination Databases

Rational drug combinations, based either on pharmacological or biological interactions, are being increasingly used in a clinical context with many effective treatments using combination therapies. Implementing beneficial drug combinations can overcome clinical challenges, including dose toxicity and drug resistance, and lead to improved therapeutic responses. Drug interactions can be classified into several types:

• Synergism – Combined effect is greater than the sum of effects seen with individual treatments
• Additivity – Observed response is the sum of the individual responses
• Potentiation – One drug does not elicit a response but enhances the effect of another drug
• Antagonistic – Exposure to one compound reduces the effect of the other

Identifying rational combinations with a clinically beneficial effect is a challenge, with the initial identification and validation based on preclinical work within cells and animal models. Towards this, several data portals including DrugComb portal and DrugcombDB4 have come online to consolidate the results of cell-line-based drug combination studies. Providing a wealth of information, these comprehensive datasets allow for the identification of synergistic combinations across different tumor types and cell lines. By intersecting commercially available drugs from the Tocris Catalog with the DrugComb portal database, we set out to identify and interrogate atypical drug combinations. Focusing on combinations with the JAK inhibitor Ruxolitinib, an FDA-approved API with multiple indications including blood cancer, we experimentally validate atypical drug combinations reported as synergistic within the Lymphoma cell line, L-1236, and explore the use of cytokines as a biomarker for synergy.