Despite the availability of numerous effective treatment options, most patients with B-cell malignancies still experience frequent relapses and progressively shorter remissions, creating a pressing need for new drugs to add to the therapeutic arsenal.
The B-cell receptor (BCR) signaling pathway, as a central regulator of B-cell function, has emerged as an exciting new anticancer drug target. Dysregulation of the pathway is a driver of many types of B-cell malignancies, and efforts to target it predominantly take aim at the abundance of readily druggable kinases that coordinate signal transmission from the BCR to downstream effectors.
The FDA’s approval of drugs targeting Bruton tyrosine kinase (BTK) and phosphoinositide-3-kinase (PI3K) provide confirmation that targeting the BCR pathway is feasible and fruitful. Although numerous challenges and questions remain unresolved, understanding of the pathway is growing and many next-generation drugs are in development (Table
aThis study is ongoing, but not recruiting participants. bThis study is not yet open for participant recruitment. AML indicates acute myeloid leukemia; BCR, B-cell receptor; BTK, Bruton tyrosine kinase; CLL, chronic lymphocytic leukemia; DLBCL, di use large B-cell lymphoma; FL, follicular lymphoma; MCL, mantle cell lymphoma; NHL, non-Hodgkin lymphoma; PI3K, phosphoinositide 3-kinase; SYK, spleen tyrosine kinase; SLL, small lymphocytic lymphoma;
The Players in B-Cell Biology
As the B cells of the immune system mature, each acquires a unique BCR on its surface. BCRs are made up of 2 parts: (1) an antigen-binding subunit composed of a membrane-bound antibody with randomly determined antigen-binding sites that allow each BCR to recognize different foreign antigens, forming the basis of the humoral immune response, and (2) a signaling subunit that triggers a signaling cascade within the B cell, regulating many important cellular functions.
The latter is a heterodimer of the CD79A and CD79B proteins, which spans the plasma membrane and contains an immunoreceptor tyrosine-based activation motif (ITAM) within the portion that protrudes into the cell.
When an antigen binds to the antibody subunit, the ITAM domains within the signaling subunit are phosphorylated by members of the SRC family of kinases, including the LYN protein. These phosphorylated domains then act as a docking platform for proteins with an SH2 domain, such as spleen tyrosine kinase (SYK).
The signal is then propagated further downstream through a complex network of interacting proteins. Central among them are PI3K and BTK. (Figure
). Ultimately, the pathway culminates in the activation of transcriptional programs within the nucleus, such as those governed by nuclear factor kappa B (NFκB) transcription factors.
This process can induce a variety of cellular responses, including survival, proliferation, and apoptosis, depending upon the nature of the antigen that initiated signaling and the stage of B-cell development, among other factors.
Taking Aim at BCR Signaling
Given how important the BCR pathway is to the functioning of normal B cells, it is unsurprising to find that its dysregulation has been implicated in the development of numerous B-cell malignancies, including chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), hairy cell leukemia (HCL), and Burkitt lymphoma (BL).
There are numerous mechanisms by which cancer cells co-opt this pathway to promote B-cell growth, proliferation, and survival. The precise molecular mechanisms involved vary among cancer types. For example, CLL cancers rarely display somatic mutations, but the BCR has been shown to be overexpressed in 30% of cases and increased expression of SYK is also common. In contrast, mutations in CD79A/B are frequently associated with DLBCL.BTK Inhibitors
The first clinical successes in targeting the BCR pathway came from drugs aimed at the BTK protein, culminating in the approval of ibrutinib (Imbruvica) in 2013 for the treatment of patients with MCL who have received at least 1 prior therapy.
BTK is a member of the TEC family of nonreceptor tyrosine kinases and is activated by SYK following BCR engagement. It is recruited to the plasma membrane by the lipid phosphatidylinositol-3,4,5-trisphosphate (PIP3
) via a part of the protein known as its pleckstrin homology domain and is then activated by LYN and SYK.
Initial approval of ibrutinib in MCL was based on the results of a multicenter, international, single-arm trial in 111 patients with previously treated disease. Ibrutinib resulted in an overall response rate (ORR) of 66%, including complete responses (CR) in 17% of patients, with a median duration of response (DOR) of 17.5 months.