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

Purpose: Waldenström's macroglobulinemia is an incurable lymphoproliferative disorder driven by an L265P mutation in the Myeloid differentiation primary response gene 88 (MYD88), which activates downstream Nuclear factor kappa-B (NF-kB) signaling through the Myddosome. As this pathway depends in part on activity of Interleukin-1 receptor-associated kinases (IRAK)-1 and -4, we sought to evaluate the potential of the IRAK1/4 inhibitor R191 in pre-clinical models. Experimental design:Patient-derived cell lines and primary samples were used in both in vitro and in vivo experiments to model Waldenström'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 Waldenström's cell lines, and suppressed activation of IRAK1/4. This was associated with cell cycle arrest at G₀/G₁, 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-kB, and of Protein kinase B/Akt/mammalian target of rapamycin signaling, while 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 Waldenström's, R191 showed anti-tumor activity. Finally, the activity of R191 was enhanced when it was combined with novel chemotherapeutics such as bortezomib, afuresertib, and ibrutinib. Conclusion:Taken together, these data support the translation of R191 as an approach to target IRAK1/4 to the clinic for Waldenström's macroglobulinemia patients.

https://ift.tt/2MsTcfm