Targeting B-cell receptor signaling: Changing the treatment landscape of B-cell Lymphoma.

ABSTRACT

Introduced in 1998, the anti-CD20 monoclonal antibody rituximab, with its unique mechanism of action, was the first agent to improve survival in patients with B-cell lymphoma (BCL) treated with chemotherapy. Laboratory investigation of the B-cell receptor signaling pathway identified the critical nature of this pathway for normal B-cell development, survival and proliferation. Further investigation showed that lymphoma cell lines were also dependent upon this pathway and hence small molecule inhibitors of critical proteins in the pathway were synthesized and shown to be cytotoxic. Subsequent translation to the clinic has shown impressive activity in some types of B-cell lymphoma. The aim of this article is to provide an overview of the constituents of the BCR signaling pathway, to illustrate how addiction to this pathway is critical for survival of some BCL, and to summarize the clinical experience with novel small molecule inhibitors of specific proteins in the BCR pathway. We speculate that combination of these agents with newer drugs, each with a unique mechanism of action might lead to improved therapy and the eventual elimination of standard chemotherapy from our therapeutic arsenal.