Identification of potential ibrutinib combinations in hematological malignancies using a combination high-throughput screen.

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 (GI50 = 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.

journal_name

Leuk Lymphoma

journal_title

Leukemia & lymphoma

authors

Schaffer M,Chaturvedi S,Davis C,Aquino R,Stepanchick E,Versele M,Liu Y,Yang J,Lu R,Balasubramanian S

doi

10.1080/10428194.2017.1349899

subject

Has Abstract

pub_date

2018-04-01 00:00:00

pages

931-940

issue

4

eissn

1042-8194

issn

1029-2403

journal_volume

59

pub_type

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