The future of B-cell lymphoma therapy: the B-cell receptor and its downstream pathways.

It is becoming increasingly apparent that tonic signaling through the B cell receptor provides a growth and survival signal in many types of B cell lymphomas, and that disruption of B cell receptor signaling can be lethal to malignant B cells. Several small molecule tyrosine kinase inhibitors, which block signaling pathways downstream from the B cell receptor, are in active clinical development. Preliminary data suggests impressive activity in relapsed and refractory B cell lymphomas. Among the kinases which have been targeted are Spleen tyrosine kinase (Syk), the Bruton's tyrosine kinase (BTK), and phosphoinositide 3-kinase (PI3K). This article discusses the rationale for targeting these pathways and summarizes the current clinical trial data for agents targeting Syk, BTK, and PI3K.