Targeting Myddosome Signaling in Waldenstrom's Macroglobulinemia with the Interleukin-1 Receptor-Associated Kinase 1/4 Inhibitor R191

Purpose: Waldenstrom's macroglobulinemia is an incurable lymphoproliferative disorder driven by an L265P mutation in the myeloid differentiation primary response gene 88 (MYD88), which activates downstream NF-kappa B signaling through the Myddosome. As this pathway depends in part on activity of interleukin-1 receptor-associated kinases (IRAKs)-1 and -4, we sought to evaluate the potential of the IRAK1/4 inhibitor R191 in preclinical models. Experimental Design: Patient-derived cell lines and primary samples were used in both in vitro and in vivo experiments to model Waldenstrom's macroglobulinemia and its response to IRAK1/4 inhibitors. Results: R191 induced a dose-and time-dependent reduction in viability of BCWM. 1 and MWCL-1 Waldenstrom's cell lines, and suppressed activation of IRAK1/4. This was associated with cell-cycle arrest at G(0)-G(1), reduced levels of cyclin-dependent kinases 4 and 6, and induction of apoptosis in cell lines and primary patient samples. Further downstream, R191 exposure led to reduced activation of NF-kappa B, and of protein kinase B/Akt/mammalian target of rapamycin signaling, whereas expression of a constitutively active Akt mutant induced R191 resistance. Gene expression profiling and gene set enrichment analysis revealed a signature consistent with inhibition of c-Myc and activation of the endoplasmic reticulum stress response. In both subcutaneous and systemic murine models of Waldenstrom's, R191 showed antitumor activity. Finally, the activity of R191 was enhanced when it was combined with novel chemotherapeutics such as bortezomib, afuresertib, and ibrutinib. Conclusions: Taken together, these data support the translation of R191 as an approach to target IRAK1/4 to the clinic for patients with Waldenstrom's macroglobulinemia. (C) 2018 AACR.