bruton's tyrosine kinase cancer

Eur J Immunol. 2005;105:259–65. Chiorazzi N, Ferrarini M. Cellular origin(s) of chronic lymphocytic leukemia: cautionary notes and additional considerations and possibilities. 2006;441:106–10. Singh SP, Pillai SY, de Bruijn MJW, Stadhouders R, Corneth OBJ, van den Ham HJ, Muggen A, van IW SE, Kuil A, et al. Phosphorylation of BTK at Y551 promotes its catalytic activity and subsequently results in its autophosphorylation at position Y223 in the SH3 domain [31]. Phospho-proteomic analysis of mantle cell lymphoma cells suggests a pro-survival role of B-cell receptor signaling. As these effects were not seen with more specific BTK inhibitor acalabrutinib that lacks ITK inhibitory activity (see below), it was concluded that the T cell expansion is unlikely to be caused by BTK inhibition [212]. 2012;489:309–12. Niemann CU, Montraveta A, Herman SEM, et al. Tam C, Grigg AP, Opat S, Ku M, Gilbertson M, Anderson MA, Seymour JF, Ritchie DS, Dicorleto C, Dimovski B, et al. Cancer Cell. Havranek O, Xu J, Kohrer S, Wang Z, Becker L, Comer JM, Henderson J, Ma W, Man Chun Ma J, Westin JR, et al. Mantle cell lymphoma. Brorson K, Brunswick M, Ezhevsky S, Wei DG, Berg R, Scott D, Stein KE. We describe clinical benefits of targeting BTK with small molecule inhibitors in B cell malignancies. Nat Immunol. Bruton's tyrosine kinase is a toll/interleukin-1 receptor domain-binding protein that participates in nuclear factor kappaB activation by toll-like receptor 4. In addition, LYN and SYK also phosphorylate tyrosine residues in the cytoplasmic tail of the B-cell co-receptor CD19 and/or the adaptor protein B-cell PI3K adaptor (BCAP), which facilitates recruitment and activation of PI3K and the guanine nucleotide exchange factor VAV [41, 42]. 1987;79:1395–400. PLoS One. BTK plays a crucial role in B cell development. 2016;387:770–8. Guo B, Kato RM, Garcia-Lloret M, Wahl MI, Rawlings DJ. 2013;37:1271–7. Cell Signal. BTK activation occurs in two steps upon its recruitment to the cell membrane. 1993;177:999–1008. Lougaris V, Baronio M, Vitali M, Tampella G, Cattalini M, Tassone L, Soresina A, Badolato R, Plebani A. Bruton tyrosine kinase mediates TLR9-dependent human dendritic cell activation. Lancet. Hing ZA, Mantel R, Beckwith KA, Guinn D, Williams E, Smith LL, Williams K, Johnson AJ, Lehman AM, Byrd JC, et al. Rudi W. Hendriks. 2008;105:13520–5. Kelly PN, Romero DL, Yang Y, Shaffer AL 3rd, Chaudhary D, Robinson S, Miao W, Rui L, Westlin WF, Kapeller R, Staudt LM. The mechanisms of PTEN inactivation include mutation, deletion or amplification of the miR17–92 microRNA cluster that downregulates PTEN expression [175, 176]. Another important branching point is induced more upstream in the BCR signaling cascade: in addition to BTK, PIP3 also interacts with PH-domain of AKT, resulting in its recruitment to the plasma membrane. Importantly, various studies confirmed empirically that administration of BTK inhibitors (Acalabrutinib and Ibrutinib) decreased the duration of mechanical ventilation and mortality rate for hospitalized patients with severe COVID-19. Upon stimulation with anti-IgM, cell size enlargement and degradation of the cyclin inhibitor p27Kip1 occurs normally, indicating that BTK is not essential for several G1 events [37]. Several genetic aberrations with prognostic value and impact on treatment decisions in CLL have been described. In line with chronic BCR-mediated signaling, CLL cells show constitutive activation of various BCR pathway associated kinases. Therefore, ibrutinib likely diminishes the immune-suppressive properties of CLL cells through both BTK-dependent and ITK-dependent mechanisms. Su YW, Zhang Y, Schweikert J, Koretzky GA, Reth M, Wienands J. Interaction of SLP adaptors with the SH2 domain of Tec family kinases. Ibrutinib treatment ameliorates murine chronic graft-versus-host disease. Rather, ibrutinib but not the more selective BTK inhibitor acalabrutinib (see below) inhibits SRC family kinases that have a critical role in platelet function [210]. In this context, it is of note that mice expressing the constitutively active BTK mutant E41K fail to form GCs [111, 112], whereas overexpression of wild-type BTK induces spontaneous GC formation [113, 114]. Phospholipase Cgamma2 is essential in the functions of B cell and several fc receptors. Approximately 50% of ABC-DLBCL harbor mutations in CARD11 or other NF-кB pathway components, including the MyD88L265P mutation [169,170,171]. Thompson EC, Cobb BS, Sabbattini P, Meixlsperger S, Parelho V, Liberg D, Taylor B, Dillon N, Georgopoulos K, Jumaa H, et al. Hyvonen M, Saraste M. Structure of the PH domain and Btk motif from Bruton's tyrosine kinase: molecular explanations for X-linked agammaglobulinaemia. Various B-cell malignancies are indicated, which are associated with abnormal BTK signaling at distinct stages of B-cell differentiation and activation. Signaling cascade showing important events downstream of (a) Chemokine receptors (e.g. Brutons tyrosine kinase in complex with compound 50. shows that U-CLL derives from unmutated mature CD5+ B cells. Curr Cancer Drug Targets. SCS macrophages suppress melanoma by restricting tumor-derived vesicle-B cell interactions. Targeting Bruton's tyrosine kinase in B cell malignancies. Cell. 2000;191:1735–44. Science. Blood. Acalabrutinib also binds C481 and lacks irreversible targeting to alternative kinases, such as EGFR, ITK, TXK, SRC family kinases and JAK3. BTK activity is crucial for survival and proliferation of leukemic B cells and for their interactions with cells in the tumor microenvironment. SYK is required for ITT phosphorylation followed by recruitment of BTK through the adapter protein Grb2, leading to enhancement of IgG BCR-induced calcium mobilization. Immunity. ADAM10 is essential for Notch2-dependent marginal zone B cell development and CD23 cleavage in vivo. 2015;212:2189–201. Belver L, de Yebenes VG, Ramiro AR. 2002;195:189–200. Bruton's tyrosine kinase (abbreviated Btk or BTK), also known as tyrosine-protein kinase BTK, is a tyrosine kinase that is encoded by the BTK gene in humans. Paradoxically, inhibiting ITK in T cells may be efficacious in cancer, as this may enhance Th1-skewing of CD4+ T-cells and thereby improved memory formation and functionality of CD8+ T-cells, potentially leading to improved anti-tumor immunity [243, 247]. Due to a severe block of B cell development in the bone marrow, XLA patients have very low numbers of B cells in the circulation and antibodies are almost completely absent in the serum. With the aim to achieve deeper remissions within a short treatment time, many ibrutinib combination therapies are currently considered (Table 2). Curr Top Microbiol Immunol. J Clin Invest. Adv Immunol. 2003;198:1539–50. 2010;17:121–34. Leuk Lymphoma. Volmering S, Block H, Boras M, Lowell CA, Zarbock A. Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL, Buchbinder A, Budman D, Dittmar K, Kolitz J, et al. First, BTK is phosphorylated at position Y551 in the kinase domain by SYK or SRC family kinases [30]. Pre-B cell receptor signaling induces immunoglobulin kappa locus accessibility by functional redistribution of enhancer-mediated chromatin interactions. Because data from BTK-deficient or inhibitor-treated myeloid cells in the context of cancer are scarce, it is not clear whether BTK inhibition by e.g. Bournazos S, Wang TT, Ravetch JV. 2013;110:E1500–7. 1998;8:635–45. N Engl J Med. Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT. This amplification loop is thought to represent a cell-intrinsic mechanism for rapid activation of class-switched memory B cells. 2011;144:646–74. Involvement of Bruton's tyrosine kinase in FcepsilonRI-dependent mast cell degranulation and cytokine production. Note that the cellular origin of U-CLL is thought to be CD5+ mature B cells. Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma. Treon SP, Xu L, Yang G, Zhou Y, Liu X, Cao Y, Sheehy P, Manning RJ, Patterson CJ, Tripsas C, et al. Another phosphatase, SH2 domain containing protein tyrosine phosphatase-1 (SHP1), has the capacity to dephosphorylate tyrosine on BTK [65]. Pathogen-specific B-cell receptors drive chronic lymphocytic leukemia by light-chain-dependent cross-reaction with autoantigens. 2012;119:4467–75. Google Scholar. Neutropenia in X-linked agammaglobulinemia. Fully activated BTK phosphorylates PLCγ2 at Y753 and Y759, which is important for its lipase activity [51]. 2012;18:3335–55. Proc Natl Acad Sci U S A. Nat Rev Immunol. Primary MCL cells show strong expression and Y223-phosphoryation of BTK [151] and in a subset of patients constitutive phosphorylation of LYN, SLP65, SYK and PKCβ [152, 153]. Bradshaw JM. volume 17, Article number: 57 (2018) Immunol Rev. Dunleavy K, Wilson WH. 4) and has a remarkably biased BCR repertoire [147]. ChemMedChem. 2010;40:2643–54. Thomas JD, Sideras P, Smith CI, Vorechovsky I, Chapman V, Paul WE. 2016;35:4368–78. 1994;91:11256–60. Yang G, Zhou Y, Liu X, Xu L, Cao Y, Manning RJ, Patterson CJ, Buhrlage SJ, Gray N, Tai YT, et al. Kinase signaling pathways represent the most common form of reversible post-translational modifications that control many aspects of cellular function. Analyses in various mouse models and in vitro studies with myeloid cells from XLA-patients clearly implicate BTK in TLR4/8/9-signaling, and possibly others [79, 225,226,227]. DAG mediates activation of protein kinase Cβ (PKCβ), which induces activation of several members of the MAPK family, including extracellular signal-regulated kinases 1 and 2 (ERK1/ERK2) and other MAPK targets, such as Jun N-terminal kinase (JNK), p38, and NF-кB pathway components [52] (Fig. See text for details. PubMed Central  Role of the inositol phosphatase SHIP in negative regulation of the immune system by the receptor fc(gamma)RIIB. Following publication of the original article [1], the authors reported an error in Table 1. Tai YT, Chang BY, Kong SY, Fulciniti M, Yang G, Calle Y, Hu Y, Lin J, Zhao JJ, Cagnetta A, et al. 2000;13:817–27. 2017;130:995–1006. 2011;43:830–7. Oncotarget. PH, pleckstrin homology; TH, TEC homology; BH, BTK homology; PRR, proline rich domain; SH2/SH3, SRC homology domains 2 and 3; Cys, cysteine-string motif. Carrier detection in X-linked agammaglobulinemia by analysis of X-chromosome inactivation. In addition, both Gα and Gβy subunits can directly bind BTK via the PH and TH domain [74, 75]. Kersseboom R, Kil L, Flierman R, van der Zee M, Dingjan GM, Middendorp S, Maas A, Hendriks RW. Tyrosine kinases Btk and Tec regulate osteoclast differentiation by linking RANK and ITAM signals. Sagiv-Barfi I, Kohrt HE, Czerwinski DK, Ng PP, Chang BY, Levy R. Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK. BTK is essential for retention of MCL cells in lymphoid tissues, since BTK inhibition induces an egress of malignant cells into peripheral blood [154]. Bruton’s tyrosine kinase (BTK) is a non-receptor kinase that plays a crucial role in oncogenic signaling that is critical for proliferation and survival of leukemic cells in many B cell malignancies. J Exp Med. Moreover, BTK is critical for BCR- and chemokine-controlled integrin-mediated retention and/or homing of CLL B cells in their microenvironment [146]. Protein Sci. J Biol Chem. Fully activated AKT then returns to the cytoplasm to enable a pro-survival signaling program that involves NFAT, forkhead transcription factors (FOXOs) and NF-кB-mediated pathways. The chemokine receptors CXCR4 and CXCR5 are expressed on B cells in different stages of their development and play important roles in trafficking, homing and homeostasis [72]. N2 - According to a Prognoscan database, upregulation of Bruton's tyrosine kinase (Btk) is associated with low overall survival in ovarian cancer patients. 2016;17:48–56. To investigate the superiority of either inhibitor, a phase III trial for direct comparison of ibrutinib with acalabrutinib in R/R CLL patients is currently ongoing (NCT02477696). Side-effects associated with off-target kinase inhibition may limit the use of ibrutinib as therapeutic agent (as discussed above). In the GCs B cells strongly proliferate and undergo somatic hypermutation (SHM) induced by activation induced cytidine deaminase (AID). Rushworth SA, Bowles KM, Barrera LN, Murray MY, Zaitseva L, MacEwan DJ. Nature. Blood. 2017;169:381–405. Kil LP, de Bruijn MJ, van Hulst JA, Langerak AW, Yuvaraj S, Hendriks RW. DLBCL is the most common form of B cell non-Hodgkin lymphomas (B-NHLs) representing ~ 30–40% of all cases. Blood. Findings from the longest follow-up reported to date, evaluating up to 5 years of ibrutinib in CLL patients, show that it is relatively safe and effective, with ~ 89% of treatment-naïve and relapsed patients experiencing a response to the therapy [206]. BTK, TEC and ITK are most similar and both contain five different protein interaction domains (Fig. Given that ibrutinib shows off-target inhibition of JAK3, ITK and EGFR [185, 207], it can be used to target oncogenic pathways other than BTK in tumor cells and as a T-cell modulator in combination immunotherapy [243,244,245,246]. Bruton tyrosine kinase-dependent immune cell cross-talk drives pancreas cancer. In particular, it was shown that ibrutinib selectively targeted pre–germinal B cells and depleted Th2 helper cells, whereby these effects persisted after drug discontinuation. https://doi.org/10.1186/s12943-018-0779-z, DOI: https://doi.org/10.1186/s12943-018-0779-z. Okada T, Maeda A, Iwamatsu A, Gotoh K, Kurosaki T. BCAP: the tyrosine kinase substrate that connects B cell receptor to phosphoinositide 3-kinase activation. Xid affects events leading to B cell cycle entry. Regulation of Btk function by a major autophosphorylation site within the SH3 domain. J Exp Med. Malcikova J, Smardova J, Rocnova L, Tichy B, Kuglik P, Vranova V, Cejkova S, Svitakova M, Skuhrova Francova H, Brychtova Y, et al. Distinct homotypic B-cell receptor interactions shape the outcome of chronic lymphocytic leukaemia. Fiedler K, Sindrilaru A, Terszowski G, Kokai E, Feyerabend TB, Bullinger L, Rodewald HR, Brunner C. Neutrophil development and function critically depend on Bruton tyrosine kinase in a mouse model of X-linked agammaglobulinemia. Btk levels set the threshold for B-cell activation and negative selection of autoreactive B cells in mice. Minici C, Gounari M, Ubelhart R, Scarfo L, Duhren-von Minden M, Schneider D, Tasdogan A, Alkhatib A, Agathangelidis A, Ntoufa S, et al. 2015;21:922–6. Tsukada S, Simon MI, Witte ON, Katz A. Oncotarget. 2018;8:OF6. Home » Cancer Topics » Hematologic Cancers » Bruton’s Tyrosine Kinase: An Exciting New Target for Treatment of B-Cell Malignancies Publish Date January 12, 2012 Consistent with the finding that these cells are important for IgM and IgG3 levels in the serum, in BTK-deficient mice IgM and IgG3 levels in serum are severely reduced, but the other isotypes are largely normal. Blood. Google Scholar. Atrial fibrillation, anticoagulant stroke prophylaxis and bleeding risk with ibrutinib therapy for chronic lymphocytic leukaemia and lymphoproliferative disorders. Copy link. Blood. Molecular Cancer Research Stereotyped patterns of somatic hypermutation in subsets of patients with chronic lymphocytic leukemia: implications for the role of antigen selection in leukemogenesis. Preclinical studies in pancreatic cancer have demonstrated promising anti-tumor activity with Bruton tyrosine kinase (BTK) inhibition combined with programmed cell death receptor-1 (PD-1) blockade. Domain structure of TEC kinase family members and key interacting partners of Bruton’s tyrosine kinase. Bolland S, Ravetch JV. Inhibitors of brutons tyrosine kinase . Hematol Oncol. Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia. Leukemia. Immunity. 1999;246:3–9. N Engl J Med. Growing evidence also suggests multiple roles for BTK in mononuclear cells of the innate immune system, especially in dendritic cells and macrophages. These include deletions of the chromosomal regions 17p13 (containing the TP53 tumor suppressor gene), 11q23 (containing DNA damage checkpoint protein ATM), or 13q14 (miR-15a, miR-16-1), and trisomy of chromosome 12 [116, 117]. EMBO J. In addition, BTK mediated signaling events are regulated by various phosphatases that can be recruited to the cell membrane, following crosslinking of inhibitory receptors, e.g., FcγRIIB that is exclusively expressed on B cells and signals upon immune complex binding. Robak P, Robak T. Novel synthetic drugs currently in clinical development for chronic lymphocytic leukemia. DOI: 10.2210/pdb6NZM/pdb; ... Optimization of novel reversible Bruton's tyrosine kinase inhibitors identified using Tethering-fragment-based screens. Chronic lymphocytic leukemia and regulatory B cells share IL-10 competence and immunosuppressive function. 2017;9:1482–90. Outlook on the Bruton's Tyrosine Kinase Inhibitors Global Industry to 2024 - Increasing Diabetic Population is Driving the Market - ResearchAndMarkets.com June 22, 2020 … Upon activation in germinal centers (GCs), B cells can perform IGH chain class switching, by which it changes Ig expression from one isotype to another with different effector function, e.g. Hendriks RW, Middendorp S. The pre-BCR checkpoint as a cell-autonomous proliferation switch. Acta Neuropathol. Murray F, Darzentas N, Hadzidimitriou A, Tobin G, Boudjogra M, Scielzo C, Laoutaris N, Karlsson K, Baran-Marzsak F, Tsaftaris A, et al. 2003;278:26258–64. Shinohara M, Koga T, Okamoto K, Sakaguchi S, Arai K, Yasuda H, Takai T, Kodama T, Morio T, Geha RS, et al. 2016;29:161–8. 2016;127:1117–27. close. DiLillo DJ, Weinberg JB, Yoshizaki A, Horikawa M, Bryant JM, Iwata Y, Matsushita T, Matta KM, Chen Y, Venturi GM, et al. Blood. BTK is essentially cytoplasmic and is only transiently recruited to the membrane through interaction of its PH domain with phosphatidylinositol-3,4,5-triphosphate (PIP3), which is generated by phosphatidylinositol-3 kinase (PI3K) (Fig. Ngo VN, Davis RE, Lamy L, Yu X, Zhao H, Lenz G, Lam LT, Dave S, Yang L, Powell J, Staudt LM. 2014;159:700–0. Accordingly, forced activation of AKT rescued GCB-DLBCL lines from knockout of the BCR or SYK and CD19, two mediators of tonic BCR signaling [174]. Nature. 2010;107:13075–80. 2001;194:1625–38. Coutre SE, Furman RR, Flinn IW, Burger JA, Blum K, Sharman J, Jones J, Wierda W, Zhao W, Heerema NA, et al. 2015;125:407–10. Btk regulates macrophage polarization in response to lipopolysaccharide. 2017;1:2610–23. J Clin Invest. Use of anticoagulants and antiplatelet in patients with chronic lymphocytic leukaemia treated with single-agent ibrutinib. Three year follow-up of ibrutinib-treated CLL patients showed that prolonged treatment was associated with improvement in response quality (the ORR increased to > 90%) and durable remission, while toxicity including cytopenia, fatigue, and infection diminished. TP53 mutation and survival in chronic lymphocytic leukemia. Oropallo MA, Cerutti A. Germinal center reaction: antigen affinity and presentation explain it all. SLP65 also mediates downregulation of SLC expression [97]. This receptor is expressed on the B cell surface and has the unique capacity to specifically recognize antigens due to hypervariable regions present in the immunoglobulin heavy (IGH) and light (IGL) chains that together form the BCR [14]. IP3 regulates intracellular calcium levels and thereby activates nuclear factor of activated T cells (NFAT) transcription, via calcineurin and calmodulin. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. Share page. 2017; Long M, Beckwith K, Do P, Mundy BL, Gordon A, Lehman AM, Maddocks KJ, Cheney C, Jones JA, Flynn JM, et al. Hammad H, Vanderkerken M, Pouliot P, Deswarte K, Toussaint W, Vergote K, Vandersarren L, Janssens S, Ramou I, Savvides SN, et al.