Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 6, Pages 2349-2354Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1311846111
Keywords
translational research; PCI-32765; Imbruvica
Categories
Funding
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences
- Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research
- Intramural Research Program of the National Human Genome Research Institute
- Intramural Research Program of the National Cancer Institute, Center for Cancer Research
- Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E, U54CA143930]
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The clinical development of drug combinations is typically achieved through trial-and-error or via insight gained through a detailed molecular understanding of dysregulated signaling pathways in a specific cancer type. Unbiased small-molecule combination (matrix) screening represents a high-throughput means to explore hundreds and even thousands of drug-drug pairs for potential investigation and translation. Here, we describe a high-throughput screening platform capable of testing compounds in pairwise matrix blocks for the rapid and systematic identification of synergistic, additive, and antagonistic drug combinations. We use this platform to define potential therapeutic combinations for the activated B-cell-like subtype (ABC) of diffuse large B-cell lymphoma (DLBCL). We identify drugs with synergy, additivity, and antagonism with the Bruton's tyrosine kinase inhibitor ibrutinib, which targets the chronic active B-cell receptor signaling that characterizes ABC DLBCL. Ibrutinib interacted favorably with a wide range of compounds, including inhibitors of the PI3K-AKT- mammalian target of rapamycin signaling cascade, other B-cell receptor pathway inhibitors, Bcl-2 family inhibitors, and several components of chemotherapy that is the standard of care for DLBCL.
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