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      Ibrutinib and novel BTK inhibitors in clinical development

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          Abstract

          Small molecule inhibitors targeting dysregulated pathways (RAS/RAF/MEK, PI3K/AKT/mTOR, JAK/STAT) have significantly improved clinical outcomes in cancer patients. Recently Bruton’s tyrosine kinase (BTK), a crucial terminal kinase enzyme in the B-cell antigen receptor (BCR) signaling pathway, has emerged as an attractive target for therapeutic intervention in human malignancies and autoimmune disorders. Ibrutinib, a novel first-in-human BTK-inhibitor, has demonstrated clinical effectiveness and tolerability in early clinical trials and has progressed into phase III trials. However, additional research is necessary to identify the optimal dosing schedule, as well as patients most likely to benefit from BTK inhibition. This review summarizes preclinical and clinical development of ibrutinib and other novel BTK inhibitors (GDC-0834, CGI-560, CGI-1746, HM-71224, CC-292, and ONO-4059, CNX-774, LFM-A13) in the treatment of B-cell malignancies and autoimmune disorders.

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          Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765.

          Sarah Herman, Amber Gordon, Erin Hertlein … (2011)
          B-cell receptor (BCR) signaling is aberrantly activated in chronic lymphocytic leukemia (CLL). Bruton tyrosine kinase (BTK) is essential to BCR signaling and in knockout mouse models its mutation has a relatively B cell-specific phenotype. Herein, we demonstrate that BTK protein and mRNA are significantly over expressed in CLL compared with normal B cells. Although BTK is not always constitutively active in CLL cells, BCR or CD40 signaling is accompanied by effective activation of this pathway. Using the irreversible BTK inhibitor PCI-32765, we demonstrate modest apoptosis in CLL cells that is greater than that observed in normal B cells. No influence of PCI-32765 on T-cell survival is observed. Treatment of CD40 or BCR activated CLL cells with PCI-32765 results in inhibition of BTK tyrosine phosphorylation and also effectively abrogates downstream survival pathways activated by this kinase including ERK1/2, PI3K, and NF-κB. In addition, PCI-32765 inhibits activation-induced proliferation of CLL cells in vitro, and effectively blocks survival signals provided externally to CLL cells from the microenvironment including soluble factors (CD40L, BAFF, IL-6, IL-4, and TNF-α), fibronectin engagement, and stromal cell contact. Based on these collective data, future efforts targeting BTK with the irreversible inhibitor PCI-32765 in clinical trials of CLL patients is warranted.
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            The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo.

            Sabine Ponader, Shih-Shih Chen, Joseph Buggy … (2012)
            B-cell receptor (BCR) signaling is a critical pathway in the pathogenesis of several B-cell malignancies, including chronic lymphocytic leukemia (CLL), and can be targeted by inhibitors of BCR-associated kinases, such as Bruton tyrosine kinase (Btk). PCI-32765, a selective, irreversible Btk inhibitor, is a novel, molecularly targeted agent for patients with B-cell malignancies, and is particularly active in patients with CLL. In this study, we analyzed the mechanism of action of PCI-32765 in CLL, using in vitro and in vivo models, and performed correlative studies on specimens from patients receiving therapy with PCI-32765. PCI-32765 significantly inhibited CLL cell survival, DNA synthesis, and migration in response to tissue homing chemokines (CXCL12, CXCL13). PCI-32765 also down-regulated secretion of BCR-dependent chemokines (CCL3, CCL4) by the CLL cells, both in vitro and in vivo. In an adoptive transfer TCL1 mouse model of CLL, PCI-32765 affected disease progression. In this model, PCI-32765 caused a transient early lymphocytosis, and profoundly inhibited CLL progression, as assessed by weight, development, and extent of hepatospenomegaly, and survival. Our data demonstrate that PCI-32765 effectively inhibits CLL cell migration and survival, possibly explaining some of the characteristic clinical activity of this new targeted agent.
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              Mechanisms of B-cell lymphoma pathogenesis.

              Ralf Küppers (2005)
              Chromosomal translocations involving the immunoglobulin loci are a hallmark of many types of B-cell lymphoma. Other factors, however, also have important roles in the pathogenesis of B-cell malignancies. Most B-cell lymphomas depend on the expression of a B-cell receptor (BCR) for survival, and in several B-cell malignancies antigen activation of lymphoma cells through BCR signalling seems to be an important factor for lymphoma pathogenesis. Recent insights into the lymphomagenic role of factors supplied by the microenvironment also offer new therapeutic strategies.
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                Author and article information

                Contributors
                Akintunde Akinleye
                Yamei Chen
                Nikhil Mukhi
                Yongping Song
                Delong Liu
                Journal
                Journal ID (nlm-ta): J Hematol Oncol
                Journal ID (iso-abbrev): J Hematol Oncol
                Title: Journal of Hematology & Oncology
                Publisher: BioMed Central
                ISSN (Electronic): 1756-8722
                Publication date Collection: 2013
                Publication date (Electronic): 19 August 2013
                Volume: 6
                Page: 59
                Affiliations
                [1 ]Division of Hematology/Oncology, Department of Medicine, New York Medical College, Valhalla, New York 10595, USA
                [2 ]Department of Hematology, Xiamen Zhongshan Hospital, Xiamen University, Xiamen, China
                [3 ]Institute of Hematology, Zhengzhou University Affiliated Tumor Hospital, Zhengzhou, China
                Article
                Publisher ID: 1756-8722-6-59
                DOI: 10.1186/1756-8722-6-59
                PMC ID: 3751776
                PubMed ID: 23958373
                SO-VID: 984d8252-7069-4c96-b80b-a8d0e705af98
                Copyright © Copyright ©2013 Akinleye et al.; licensee BioMed Central Ltd.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 27 July 2013
                Date accepted : 18 August 2013
                Categories
                Subject: Review

                ScienceOpen disciplines: Oncology & Radiotherapy
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy

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