Inhibitors of B-cell receptor signaling for patients with B-cell malignancies

Abstract

The B-cell receptor (BCR) complex and its associated protein tyrosine kinases play a critical role in the development, proliferation, and survival of normal or malignant B cells. Regulated activity of the BCR complex promotes the expansion of selected B cells and the deletion of unwanted or self-reactive ones. Compounds that inhibit various components of this pathway, including spleen tyrosine kinase, Bruton's tyrosine kinase, and phosphoinositol-3 kinase, have been developed. We summarize the rationale for use of agents that can inhibit BCR signaling to treat patients with either indolent or aggressive B-cell lymphomas, highlight early clinical results, and speculate on the future application of such agents in the treatment of patients with various B-cell lymphomas.

Figure 1

Schema for B-cell receptor (BCR) mediated signaling in B-cell lymphoma. The BCR complex consists of surface Ig and accessory molecules CD79a and CD79b, which are phosphorylated in response to antigen binding, and recruit Syk to the activated complex. Syk activates downstream adapter proteins and molecules such as BLNK, Btk, and PLCγ2, which ultimately promotes cell survival and proliferation by various downstream pathways. BCR activation also triggers Lyn dependent phosphorylation of CD19, which provides a docking site of PI3K, leading to activation of AKT, which modulates pathways including mTOR and NF-κB. Molecules that play an inhibitory role include FcγRIIB, which recruit and activate SHIP and other phosphatases that reset the activation cascade.