1. Identification of potential ibrutinib combinations in hematological malignancies using a combination high-throughput screen.
- Author
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Schaffer, Michael, Chaturvedi, Shalini, Davis, Cuc, Aquino, Regina, Stepanchick, Emily, Balasubramanian, Sriram, Versele, Matthias, Liu, Yang, Yang, Jennifer, and Lu, Rongzhen
- Subjects
BCL-2 proteins ,DIFFUSE large B-cell lymphomas ,MEDICAL screening ,COMBINATION drug therapy ,PROTEIN-tyrosine kinases - Abstract
Matrix high-throughput screening (HTS) methods are increasingly employed to rapidly define potential therapeutic drug combinations. We used combination HTS to identify compounds showing synergistic anti-proliferative activity with ibrutinib, an irreversible, small-molecule inhibitor of Bruton’s tyrosine kinase. The goal was to identify ibrutinib combinations with maximum synergistic effects in heme malignancy lines, particularly in non-Hodgkin lymphoma including diffuse large B-cell lymphoma (DLBCL). Growth inhibition (GI) was used to measure cell viability; synergy scores characterized strength of synergistic interaction. Single-agent ibrutinib demonstrated varying degrees of activity across 30 cell lines evaluated. In DLBCL lines, TMD8 was the most sensitive to ibrutinib (GI
50 = 0.001); combinations with BCL-2 inhibitor ABT-199, and PI3K inhibitors IPI-145 and GDC-0941 showed the strongest synergistic activity. Anti-proliferative synergies were also observed with BET bromodomain inhibitor (+)-JQ1, XPO1 inhibitor selinexor, and IRAK4 inhibitor, and confirmed using apoptosis assay. These findings are intended to inform and advance treatment of B-cell malignancies. [ABSTRACT FROM AUTHOR]- Published
- 2018
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