Defining principles of combination drug mechanisms of action.

TitleDefining principles of combination drug mechanisms of action.
Publication TypeJournal Article
Year of Publication2013
AuthorsPritchard, JR, Bruno, PM, Gilbert, LA, Capron, KL, Lauffenburger, DA, Hemann, MT
JournalProc Natl Acad Sci U S A
Date Published2013 Jan 8
KeywordsAnimals, Biological Markers, Drug Combinations, Drug Design, Drug Synergism, Genetic Variation, Humans, Mice, Neoplasms, Principal Component Analysis, RNA Interference, Systems Biology

Combination chemotherapies have been a mainstay in the treatment of disseminated malignancies for almost 60 y, yet even successful regimens fail to cure many patients. Although their single-drug components are well studied, the mechanisms by which drugs work together in clinical combination regimens are poorly understood. Here, we combine RNAi-based functional signatures with complementary informatics tools to examine drug combinations. This approach seeks to bring to combination therapy what the knowledge of biochemical targets has brought to single-drug therapy and creates a statistical and experimental definition of "combination drug mechanisms of action." We show that certain synergistic drug combinations may act as a more potent version of a single drug. Conversely, unlike these highly synergistic combinations, most drugs average extant single-drug variations in therapeutic response. When combined to form multidrug regimens, averaging combinations form averaging regimens that homogenize genetic variation in mouse models of cancer and in clinical genomics datasets. We suggest surprisingly simple and predictable combination mechanisms of action that are independent of biochemical mechanism and have implications for biomarker discovery as well as for the development of regimens with defined genetic dependencies.

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID23251029
PubMed Central IDPMC3545813
Grant ListR01 CA128803 / CA / NCI NIH HHS / United States
R01-CA128803-04 / CA / NCI NIH HHS / United States
U54 CA112967 / CA / NCI NIH HHS / United States
U54-CA112967-06 / CA / NCI NIH HHS / United States