High throughput in vitro combination sensitivity screen in hematologic malignancies with the phosphoinositide-3 kinase (PI3K)-δ,γ inhibitor, duvelisib.

Abstract

8559 Background: Signaling via PI3K-δ and PI3K-γ has distinct and complementary effects on the tumor cell/ tumor microenvironment in hematologic malignancies (HM). Duvelisib (IPI-145) is an orally active inhibitor of the PI3K-δ and PI3K-γ isoforms in clinical development in HM. To gain mechanistic insights into the cellular response to duvelisib and identify novel pairings for duvelisib in HM, a high-throughput in vitro combination screen was conducted. Methods: Duvelisib was evaluated alone and in combination with 35 compounds comprising a diverse panel of standard-of-care agents and emerging drugs in development for HM. These compounds were tested in 20 cell lines including diffuse large B-cell (DLBCL), follicular, T-cell, and mantle cell lymphomas, and multiple myeloma. Growth inhibition (GI) was measured by ATPLite (Perkin Elmer) in a 6x6 or 9x9 dose combination matrix. Results: Single agent activity was seen in 14 cell lines treated with duvelisib, with a median GI50 of 0.59 µM. A scalar measure of t...