Bruton's tyrosine kinase: oncotarget in myeloma

Yu-Tzu Tai,Kenneth C Anderson

doi:10.18632/oncotarget.655

Abstract

Our findings therefore provide a strong rationale for investigating Btk inhibitors in MM and WM to target both tumor cells and their supporting BM microenvironment and thereby both suppress tumor cell growth and abrogate MM-induced bone disease.

Highlights

Targeting Bruton’s tyrosine kinase (Btk), an essential element of B cell receptor (BCR) signaling pathway, has achieved remarkable efficacy with an acceptable safety profile in B cell malignancies
Ibrutinib-induced inactivation of Btk and downstream NFκB and STAT3 is correlated with tumor cell cytotoxicity
Our studies further show that Waldenstrom’s macroglobulinemia (WM) cells express CD19 and BCR, which mediate growth and survival, whereas MM cells lack both, accounting, at least in part, for the greater direct cytotoxicity of Ibrutinib against WM than MM cells

Summary

Introduction

Targeting Bruton’s tyrosine kinase (Btk), an essential element of B cell receptor (BCR) signaling pathway, has achieved remarkable efficacy with an acceptable safety profile in B cell malignancies. B cell receptor signaling and Btk expression on normal plasma cells and MM cells is unexpected.[2] our recent studies using gene expression profiling and immunoblotting demonstrated robust Btk expression in the majority (>85%) of patient MM cells and in all tumor cells from patients with Waldenstrom’s macroglobulinemia (WM).[3] Importantly, Ibrutinib effectively blocked both baseline and induced activation of Btk and downstream NFκB, STAT3, ERK1/2, and Akt signaling pathways mediating tumor cell proliferation and survival.

Results

Conclusion