Preclinical Evaluation Of A Novel Interleukin-1 Receptor-Associated Kinase 4 (Irak4) Inhibitor In Combination With Pi3k Inhibitor Copanlisib Or Btk Inhibitors In Abc-Dlbcl

Activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is frequently characterized by aberrant activation of both B-Cell Receptor (BCR) u0026 TLR/MYD88 signaling pathways. Constitutive BCR signaling via Bruton9s tyrosine kinase (BTK) and PI3K pathways leads to downstream activation of NF-κB and AKT signaling. In addition, IRAK4 mediated activation of the TLR/MYD88 pathway further activates NF-κB signaling and pro-survival pathways. Simultaneous blockade of TLR/MYD88 signaling via IRAK4 inhibition in combination with pharmacological blockade of PI3K/BCR signaling pathways may therefore provide a novel treatment strategy in ABC-DLBCL. BAY 1830839 is a novel small molecule inhibitor of IRAK4 identified by a medicinal chemistry optimization program. Key features of the compound are high potency (IC 50 of 3 nM) in a biochemical assay, excellent kinase selectivity and a good overall PK profile making the compound a valuable tool for in vivo studies. In vitro, treatment of IRAK4 inhibitor BAY 1830839 in combination with BTK inhibitors or copanlisib, a pan class I PI3K inhibitor with predominant activity towards PI3Kα and PI3Kδ, synergistically inhibited NF-κB activation and cell viability in human ABC-DLBCL cell lines. In vivo, IRAK4 inhibition alone did not exhibit anti-tumor effects but in combination treatment with ibrutinib, a covalent inhibitor of BTK, synergistic anti-tumor activity with significantly improved efficacy over ibrutinib monotherapy was observed in the human ABC-DLBCL xenograft models TMD-8 and OCI-LY10 (MYD88 mut /CD79A/B mut ). Moreover, IRAK4 inhibitor BAY 1830839 showed synergistic anti-tumor activity in combination with copanlisib with significant improvement of copanlisib monotherapy efficacy in the ABC-DLBCL PDX models LY2988 and LY2266 (MYD88 mut /CD79A/B mut and MYD88 wt /CD79A/B wt , respectively). In addition, the combination of IRAK4 inhibition with pharmacological blockade of PI3K-/ BCR signaling led to reduced activity of the downstream pro-survival STAT3 pathway and IL-6/IL-10 production as detected in tumor xenografts, validating our biological rationale and the expected mechanism of action. In summary, IRAK4 inhibition in combination with pharmacological blockade of PI3K or BCR signaling blocks pro-survival NF-κB u0026 JAK-STAT pathway activation and subsequent IL-6/IL-10 production. Enhancing activity of clinically used PI3K or BTK inhibitors by combination with IRAK4 inhibition indicates a potential new treatment approach for ABC-DLBCL patients progressing on Standard of Care therapy. Citation Format: Martin Lange, Antje Margret Wengner, Ulrich Bothe, Ulf Boemer, Reinhard Nubbemeyer, Holger Siebeneicher, Holger Steuber, Judith Guenther, Lisette Potze, Nicole Schmidt, Oliver Politz, Wolf-Dietrich Doecke, Eleni Lagkadinou, Thomas M. Zollner, Franz von Nussbaum, Dominik Mumberg, Andreas Steinmeyer, Michael Brands, Karl Ziegelbauer. Preclinical evaluation of a novel interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor in combination with PI3K inhibitor copanlisib or BTK inhibitors in ABC-DLBCL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1887.