Abstract 2686: Dual inhibition of BCR and TLR signaling has therapeutic potential in chronic lymphocytic leukemia

Introduction: The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib is clinically active in lymphoproliferative diseases driven by B-cell receptor (BCR) and Toll-like receptor (TLR) signaling, including chronic lymphocytic leukemia (CLL) and Waldenstrom macroglobulinemia (WM), respectively. However, deep remissions are uncommon and resistance to single agent has been described. The hallmark of WM is an activating mutation in MYD88 in the TLR signaling pathway. While mutations in MYD88 are uncommon in CLL, our previous study identified gene signatures indicative of active BCR and TLR signaling in CLL cells residing in lymphoid tissues (Herishanu, Blood 2011). Further, TLR9 activating CpG oligonucleotides induce proliferation and extend CLL cell survival in vitro. These observations suggest that BCR and TLR signaling may cooperate to activate CLL cells in the tissue microenvironment. Here, we tested the hypothesis that targeting both BCR and TLR signaling could improve therapy for CLL. Methods: CLL PBMCs were treated with ibrutinib and/or an IRAK1/4 inhibitor (Calbiochem) for 1h and then stimulated with soluble αIgM, CpG, or both. We quantified changes in phosphorylation of BTK, PLCγ2 and ERK (BCR pathway) and STAT3 and STAT1, as well as total IRAK1 (TLR pathway). Results: As expected, ibrutinib inhibited phosphorylation of BTK, PLCγ2 and ERK (P Conclusion: While ibrutinib partially inhibited TLR signaling, an IRAK1/4 inhibitor was required for full inhibition of the pathway. The combination of BTK and IRAK1/4 inhibition for the treatment of lymphoproliferative diseases warrants further investigation. Citation Format: Eman L. Dadashian, Sarah Herman, Adrian Wiestner. Dual inhibition of BCR and TLR signaling has therapeutic potential in chronic lymphocytic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2686. doi:10.1158/1538-7445.AM2017-2686