Key Elements of BTK Signaling
BCR indicates B-cell receptor; BTK, Bruton tyrosine kinase. Source: GeneCards, www.genecards.org.
A greater understanding of the molecular mechanisms underlying lymphoid malignancies has fostered the development of targeted therapies, including those aimed at B-cell signaling pathways. In the past few years, overwhelmingly positive results have been observed with small-molecule inhibitors of Bruton tyrosine kinase (BTK), a downstream component of B-cell antigen receptor (BCR) signaling.
The excitement over these new agents has been growing since the FDA approved ibrutinib (Imbruvica) as a treatment for mantle cell lymphoma (MLC) late last year under the agency’s Breakthrough Therapy program. In mid-February, ibrutinib gained approval for patients with chronic lymphocytic leukemia (CLL) who have received at least one previous therapy.
BTK-targeted agents have the potential to alter the treatment landscape for patients with lymphoma and leukemia and, indeed, we are already beginning to see treatment guidelines adapted.
BTK: A Key Conduit of BCR Signaling Pathways
The proliferation, differentiation, and survival of the B cells of the immune system are controlled by biochemical signals transmitted via the BCR, an antigen-specific receptor protein found in the membrane of these cells. Binding of a specific antigen to the immunoglobulin component of the BCR triggers a cascade of downstream molecules to become activated. Among them is BTK, a nonreceptor tyrosine kinase that was originally discovered in the early 1950s by the American pediatrician Ogden C. Bruton, MD, who linked BTK to a rare X-linked immunodeficiency syndrome.
BTK is expressed on other hematopoietic cells, including macrophages and neutrophils, though not on T cells or normal plasma cells, and is involved in the activation of a number of other signaling pathways; however, its best understood canonical role is in the BCR pathway. BTK is typically found in the cytoplasm but moves to the membrane during B-cell activation, whereupon it is phosphorylated by a number of different kinases. In turn, BTK then phosphorylates a range of downstream targets, ultimately resulting in the activation of cellular pathways that govern vital B-cell processes.
Although the gene that encodes BTK is not considered a classical oncogene, the inappropriate activation of BTK has been demonstrated to be involved in the maintenance of a wide variety of malignancies; for example, constitutive activation of BTK is an absolute prerequisite for the development of CLL, but BTK mutations have also been identified in patients with acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and more recently, in solid tumors such as colorectal carcinoma. As such, researchers recognized the potential for developing BTK-targeted anticancer agents and the class has become an area of substantial clinical interest in recent years.
Emergence of Ibrutinib
Among the earliest small-molecule inhibitors of BTK to be described was LFM-A13. This agent was widely used in preclinical studies, but mostly to further delineate the cellular role of BTK. Since the agent also inhibited polo-like kinase (PLK) and Janus kinase (JAK) 2, it has not progressed beyond this stage of development. Things really began to move forward in this field after Zhengying Pan, PhD, now at Peking University, and colleagues designed ibrutinib in the mid-2000s. The compound, formerly identified as PCI-32765, is a small molecule that irreversibly inhibits BTK enzymatic activity by covalently binding to cysteine- 481 in the tyrosine kinase domain.
Following promising preclinical studies in which it displayed dose- and time-dependent cytotoxicity in tumor cells, ibrutinib entered clinical trials. At the phase I stage, it was shown to be highly efficacious and safe in various B-cell malignancies. Both intermittent and continuous dosing schedules demonstrated similar efficacy and toxicity. However, a continuous dosing schedule was ultimately pursued in later trials since there was a possibility of reversed effects during the off-drug days with an intermittent schedule.
Phase I and II trials in a range of different lymphoid malignancies subsequently began, many of which are still ongoing. In November 2013, positive results from a phase II trial led to ibrutinib’s approval in MCL. The subsequent approval in CLL was based on phase IB/II clinical trial results. Ibrutinib also has been designated as a Breakthrough Therapy in Waldenström macroglobulinemia.
A multitude of phase III clinical trials of ibrutinib are under way in the hopes of expanding the indications of this agent. Ibrutinib is currently approved for use as a single agent in MCL and CLL, and many trials continue to evaluate its efficacy as mono therapy.