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      Targeting B-cell receptor signaling kinases in chronic lymphocytic leukemia: the promise of entospletinib

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          Abstract

          The B-cell receptor signaling pathway has emerged as an important therapeutic target in chronic lymphocytic leukemia and other B-cell malignancies. Novel agents have been developed targeting the signaling enzymes spleen tyrosine kinase (SYK), Bruton’s tyrosine kinase, and phosphoinositide 3-kinase delta. This review discusses the rationale for targeting these enzymes, as well as the preclinical and clinical evidence supporting their role as therapeutic targets, with a particular focus on SYK inhibition with entospletinib.

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          Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib.

          Jennifer A. Woyach, Richard R Furman, Ta-Ming Liu … (2014)
          Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (BTK) and is effective in chronic lymphocytic leukemia (CLL). Resistance to irreversible kinase inhibitors and resistance associated with BTK inhibition have not been characterized. Although only a small proportion of patients have had a relapse during ibrutinib therapy, an understanding of resistance mechanisms is important. We evaluated patients with relapsed disease to identify mutations that may mediate ibrutinib resistance. We performed whole-exome sequencing at baseline and the time of relapse on samples from six patients with acquired resistance to ibrutinib therapy. We then performed functional analysis of identified mutations. In addition, we performed Ion Torrent sequencing for identified resistance mutations on samples from nine patients with prolonged lymphocytosis. We identified a cysteine-to-serine mutation in BTK at the binding site of ibrutinib in five patients and identified three distinct mutations in PLCγ2 in two patients. Functional analysis showed that the C481S mutation of BTK results in a protein that is only reversibly inhibited by ibrutinib. The R665W and L845F mutations in PLCγ2 are both potentially gain-of-function mutations that lead to autonomous B-cell-receptor activity. These mutations were not found in any of the patients with prolonged lymphocytosis who were taking ibrutinib. Resistance to the irreversible BTK inhibitor ibrutinib often involves mutation of a cysteine residue where ibrutinib binding occurs. This finding, combined with two additional mutations in PLCγ2 that are immediately downstream of BTK, underscores the importance of the B-cell-receptor pathway in the mechanism of action of ibrutinib in CLL. (Funded by the National Cancer Institute and others.).
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            PI3K in lymphocyte development, differentiation and activation.

            Klaus Okkenhaug, Bart Vanhaesebroeck (2003)
            Phosphoinositide 3-kinases (PI3Ks) regulate numerous biological processes, including cell growth, differentiation, survival, proliferation, migration and metabolism. In the immune system, impaired PI3K signalling leads to immunodeficiency, whereas unrestrained PI3K signalling contributes to autoimmunity and leukaemia. New insights into the role of PI3Ks in lymphocyte biology have been derived from gene-targeting studies, which have identified the PI3K subunits that are involved in B-cell and T-cell signalling. In particular, the catalytic subunit p110delta seems to be adapted to transmit antigen-receptor signalling in B and T cells. Additional recent work has provided new insights into the molecular interactions that lead to PI3K activation and the signalling pathways that are regulated by PI3K.
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              Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia.

              Jonathan W. Friedberg, Jeff Sharman, John Sweetenham … (2010)
              Certain malignant B cells rely on B-cell receptor (BCR)-mediated survival signals. Spleen tyrosine kinase (Syk) initiates and amplifies the BCR signal. In in vivo analyses of B-cell lymphoma cell lines and primary tumors, Syk inhibition induces apoptosis. These data prompted a phase 1/2 clinical trial of fostamatinib disodium, the first clinically available oral Syk inhibitor, in patients with recurrent B-cell non-Hodgkin lymphoma (B-NHL). Dose-limiting toxicity in the phase 1 portion was neutropenia, diarrhea, and thrombocytopenia, and 200 mg twice daily was chosen for phase 2 testing. Sixty-eight patients with recurrent B-NHL were then enrolled in 3 cohorts: (1) diffuse large B-cell lymphoma (DLBCL), (2) follicular lymphoma (FL), and (3) other NHL, including mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), mucosa-associated lymphoid tissue lymphoma, lymphoplasmacytic lymphomas, and small lymphocytic leukemia/chronic lymphocytic leukemia (SLL/CLL). Common toxicities included diarrhea, fatigue, cytopenias, hypertension, and nausea. Objective response rates were 22% (5 of 23) for DLBCL, 10% (2 of 21) for FL, 55% (6 of 11) for SLL/CLL, and 11% (1/9) for MCL. Median progression-free survival was 4.2 months. Disrupting BCR-induced signaling by inhibiting Syk represents a novel and active therapeutic approach for NHL and SLL/CLL. This trial was registered at www.clinicaltrials.gov as #NCT00446095.
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                Author and article information

                Contributors
                Jeff Sharman
                Julie Di Paolo
                Journal
                Journal ID (nlm-ta): Ther Adv Hematol
                Journal ID (iso-abbrev): Ther Adv Hematol
                Journal ID (publisher-id): TAH
                Journal ID (hwp): sptah
                Title: Therapeutic Advances in Hematology
                Publisher: SAGE Publications (Sage UK: London, England )
                ISSN (Print): 2040-6207
                ISSN (Electronic): 2040-6215
                Publication date (Electronic): 17 March 2016
                Publication date (Print): June 2016
                Volume: 7
                Issue: 3
                Pages: 157-170
                Affiliations
                [1-2040620716636542]Willamette Valley Cancer Institute and Research Center, US Oncology Research, 3377 Riverbend Drive, Suite 500, Springfield, OR 97477, USA
                [2-2040620716636542]Department of Biology, Gilead Sciences, Inc., Foster City, CA, USA
                Author notes
                Article
                Publisher ID: 10.1177_2040620716636542
                DOI: 10.1177/2040620716636542
                PMC ID: 4872176
                PubMed ID: 27247756
                SO-VID: e2eb1458-5b5d-467a-81a6-0981d8cf2d3f
                Copyright © © The Author(s), 2016
                License:

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License ( http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

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                Categories
                Subject: Reviews

                ScienceOpen disciplines: Hematology
                Keywords: b-cell receptor signaling inhibitors,chronic lymphocytic leukemia,entospletinib,idelalisib,lymphoid malignancies,phosphoinositide 3-kinase delta,spleen tyrosine kinase inhibitors
                Data availability:
                ScienceOpen disciplines: Hematology
                Keywords: b-cell receptor signaling inhibitors, chronic lymphocytic leukemia, entospletinib, idelalisib, lymphoid malignancies, phosphoinositide 3-kinase delta, spleen tyrosine kinase inhibitors

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