The B-cell receptor signaling pathway as a therapeutic target in CLL

Abstract

Targeted therapy with imatinib and other selective tyrosine kinase inhibitors has transformed the treatment of chronic myeloid leukemia. Unlike chronic myeloid leukemia, chronic lymphocytic leukemia (CLL) lacks a common genetic aberration amenable to therapeutic targeting. However, our understanding of normal B-cell versus CLL biology points to differences in properties of B-cell receptor (BCR) signaling that may be amenable to selective therapeutic targeting. The application of mouse models has further expanded this understanding and provides information about targets in the BCR signaling pathway that may have other important functions in cell development or long-term health. In addition, overexpression or knockout of selected targets offers the potential to validate targets genetically using new mouse models of CLL. The initial success of BCR-targeted therapies has promoted much excitement in the field of CLL. At the present time, GS-1101, which reversibly inhibits PI3Kδ, and ibrutinib (PCI-32765), an irreversible inhibitor of Bruton tyrosine kinase, have generated the most promising early results in clinical trials including predominately refractory CLL where durable disease control has been observed. This review provides a summary of BCR signaling, tools for studying this pathway relevant to drug development in CLL, and early progress made with therapeutics targeting BCR-related kinases.

Figure 1

B-cell receptor signaling in CLL. (A) The BCR is composed of membrane immunoglobulin bound to CD79a/CD79b. Antigen binding induces CD79a/CD79b ITAM recruitment of Syk and Lyn initiating the signaling cascade. (B) Signalosome complex. Phosphorylation of CD79a/CD79b recruits a number of kinases and adaptor proteins, which form the initial signaling complex of the BCR. (C) Intermediate activation. Signalosome activation recruits a number of additional kinases leading to activation down 3 main pathways: Btk, PLC-γ2, and PI3K. Btk is phosphorylated by itself; Syk, and Lyn, which lead to phosphorylation of PLC-γ2, activation of NFκB; and recruitment of PIP5K. PLC-γ2 is phosphorylated by Btk and Syk and leads to production of DAG and IP3. PI3K activation leads to phosphorylation of PIP2 to PIP3.

Figure 2

Integrin signaling in CLL. (A) Inside-out integrin signaling. Signaling through the BCR, dependent on Btk and PLC-γ2, activates the cytoplasmic domain of the integrin, causing a conformational change to the open, active form. This form has high affinity for ligand binding and induces cell migration and adhesion. (B) Outside-in integrin signaling. Ligand binding to an integrin induces signals that can lead to growth, differentiation, survival, or apoptosis.

Figure 3

Kinase inhibitors in CLL. (A) Chemical structures of signal kinase inhibitors. (B) Kinase inhibitors and the BCR pathway.