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REVIEW

BCR Signaling in Chronic Lymphocytic Leukemia and Related Inhibitors Currently in Clinical Studies

, MD, PhD & , MD, PhD
Pages 358-376 | Accepted 06 Mar 2013, Published online: 25 Apr 2013

REFERENCES

  • Hallek M, Cheson D, Catovsky D, Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 Guidelines. Blood 2008;111:5446–5456.
  • Siegel R, DeSantis C, Virgo K, Cancer treatment and survivorship statistics 2012. CA Cancer J Clin 2012;62:220–241.
  • Robak T, Jamroziak K, Robak P. Current and emerging treatments for chronic lymphocytic leukaemia. Drugs 2009;69:2415–2449.
  • Montiilo M, Hamblin T, Hallek M Chronic lymphocytic leukemia: novel prognostic factors and their relevance for risk-adapted therapeutic strategies. Haematologica 2005;90:391–399.
  • Damle RN, Wasil T, Fais F, Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 1999;94:1840–1847.
  • Hamblin TJ, Orchard JA, Ibbotson RE, CD38 expression and immunoglobulin variable region mutations are independent prognostic variables in chronic lymphocytic leukemia, but CD38 expression may vary during the course of the disease. Blood 2002;99:1023–1029.
  • Dohner H, Stilgenbauer S, Benner A, Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000;343:1910–1916.
  • Byrd JC, Gribben JG, Peterson BL Select high-risk genetic features predict earlier progression after chemoimmunotherapy with fludarabine and rituximab in chronic lymphocytic leukemia: justification for risk-adapted therapy. J Clin Oncol 2006;24:437–443.
  • Robak T, Robak E. Tyrosine kinase inhibitors as potential drugs for B-cell lymphoid malignancies and autoimmune disorders. Expert Opin Investig Drugs 2012;21:921–947.
  • Stevenson FK, Krysov S, Paterson A, B-cell receptor signaling in chronic lymphocytic leukemia. Blood (ASH Annual Meeting Abstracts). 2012;120:SCI-25.
  • Pierce SK, Liu W. The tipping points in the initiation of B-cell signalling: how small changes make big differences. Nat Rev Immunol 2010;10:767–777.
  • Niiro H, Clark EA. Regulation of B-cell fate by antigen-receptor signals. Nat Rev Immunol 2002;2:945–956.
  • Efremov DG, Wiestner A, Laurenti L. Novel agents and emerging strategies for targeting the B-cell receptor pathway in CLL. Mediterr J Hematol Infect Dis 2012;4:e2012067. doi: 10.4084/MJHID.2012.067.
  • Monroe JG. ITAM-mediated tonic signalling through pre-BCR and BCR complexes. Nat Rev Immunol. 2006;6:283–294.
  • Packham G, Stevenson F. The role of the B-cell receptor in the pathogenesis of chronic lymphocytic leukaemia. Semin Cancer Biol 2010;20:391–399.
  • Quiroga MP, Balakrishnan K, Kurtova AV B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406. Blood 2009;114:1029–1037.
  • Buchner M, Fuchs S, Prinz G, Spleen tyrosine kinase is overexpressed and represents a potential therapeutic target in chronic lymphocytic leukemia. Cancer Res 2009;69:5424–5432.
  • Bernal A, Pastore RD, Asgary Z, Survival of leukemic B cells promoted by engagement of the antigen receptor. Blood 2001;98:3050–3057.
  • Dühren-von Minden M, Übelhart R, Schneider D, Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomoussignalling. Nature 2012;489:309–312.
  • Baudot AD, Jeandel PY, Mouska X, The tyrosine kinase Syk regulates the survival of chronic lymphocytic leukemia B cells through PKCdelta and proteasome-dependent regulation of Mcl-1 expression. Oncogene 2009;28:3261–3273.
  • Herman SE, Gordon AL, Hertlein E, Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood 2011;117:6287–6296.
  • Barragán M, Bellosillo B, Campàs C, Involvement of protein kinase C and phosphatidylinositol 3-kinase pathways in the survival of B-cell chronic lymphocytic leukemia cells. Blood 2002;99:2969–2976.
  • Muzio M, Apollonio B, Scielzo C, Constitutive activation of distinct BCR-signaling pathways in a subset of CLL patients: a molecular signature of anergy. Blood 2008;112:188–195.
  • Wiestner A. Targeting B-cell receptor signaling for anticancer therapy: The Bruton'styrosine kinase inhibitor ibrutinibinduces impressive responses in B-cell malignancies. J Clin Oncol 2013;31:128–130.
  • Winer ES, Ingham RR, Castillo JJ. PCI-32765: a novel Bruton's tyrosine kinase inhibitor for the treatment of lymphoid malignancies. Expert OpinInvestig Drugs 2012;21:355–361
  • Darzentas N, Stamatopoulos K. Stereotyped B-cell receptors in B-cell leukemiasand lymphomas. Methods Mol Biol 2013;971:135–148.
  • Agathangelidis A, Darzentas N, Hadzidimitriou A, Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies. Blood 2012;119:4467–4475.
  • Stamatopoulos K, Belessi C, Moreno C, Over 20% of patients with CLL carry 0stereotyped receptors: pathogenetic implications and clinical correlations. Blood 2007;109:259–270.
  • Hoogeboom R, van Kessel KP, Hochstenbach F, A mutated B-cell chronic lymphocytic leukemia subset that recognizes and responds to fungi. J Exp Med 2013;210:59–70.
  • Wiestner A. Emerging role of kinase-targeted strategies in chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program 2012;2012:88–96.
  • Woyach JA, Johnson AJ, Byrd JC. The B-cell receptor signaling pathway as a therapeutic target in CLL. Blood 2012;120(6):1175–1184.
  • Robak P, Robak T. A targeted therapy for protein and lipid kinases in chronic lymphocytic leukemia. Curr Med Chem 2012;19:5294–5318.
  • Binder M, Müller F, Frick M, CLL B-cell receptors can recognize themselves: alternative epitopes and structural clues for autostimulatory mechanisms in CLL. Blood 2013;121: 239–241.
  • Genevier HC, Hinshelwood S, Gaspar HB, Expression of Bruton's tyrosine kinase protein within the B-cell lineage. Eur J Immunol 1994;24:3100–3105.
  • Mohamed AJ, Yu L, Bäckesjö CM, Bruton's tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain. Immunol Rev 2009;228:58–73.
  • Afar DE, Park H, Howell BW Regulation of Btk by Src family tyrosine kinases. Mol Cell Biol 1996;16:3465–3471.
  • Cheng G, Ye ZS, Baltimore D. Binding of Bruton's tyrosine kinase to Fyn, Lyn, or Hck through a Src homology 3 domain-mediated interaction. Proc Natl Acad Sci USA 1994;91:8152–8155.
  • Satterthwaite AB, Li Z, Witte ON. Btk function in B-cell development and response. Semin Immunol 1998;10:309–316.
  • Brown JR. Ibrutinib (PCI-32765), the First BTK (Bruton's Tyrosine Kinase) inhibitor in clinical trials. Cur Hematol Malig Rep 2013. [Epub ahead of print]
  • Pan Z, Scheerens H, Li S, Discovery of selective irreversible inhibitors for Bruton's tyrosine kinase. Chem Med Chem 2007;2:58–61.
  • Davis RE, Ngo VN, Lenz G, Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 2010;463:88–92.
  • Honigberg LA, Smith AM, Sirisawad M, The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci USA 2010;107:13075–13080.
  • de Rooij MF, Kuil A, Geest CR The clinically active BTK inhibitor PCI-32765 targets B-cellreceptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood 2012;119:2590–2594.
  • Ponader S, Chen SS, Buggy JJ, The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood 2012;119:1182–1189.
  • Brown JR. Ibrutinib (PCI-32765), the First BTK (Bruton's Tyrosine Kinase) inhibitor in clinical trials. Curr Hematol Malig Rep 2013;8:1–6.
  • Wang YL, Cheng S, Ma J, BTK inhibition targets in vivo CLL proliferation through its effects on B-cell receptor signaling activity. Blood (ASH Annual Meeting Abstracts), 2012;120:2903.
  • Herman SE, Farooqui M, Bezabhie R In vivo effects of ibrutinib on BCR signaling, tumor cell activation and proliferation in blood and tissue-resident cells of chronic lymphocytic leukemia patients. Blood (ASH Annual Meeting Abstracts), 2012;120:185.
  • Burger JA, O'Brien S, Fowler N, The Bruton's tyrosine kinase inhibitor, PCI-32765, is well tolerated and demonstrates promising clinical activity in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL): an update on ongoing phase 1 studies. Blood 2010;116: 32a.
  • Byrd JC, Furman RR, Coutre S, The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib (PCI-32765) promotes high response rate, durable remissions, and is tolerable in treatment naïve (TN) and relapsed or refractory (RR) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) patients including patients with high-risk (HR) disease: new and updated results of 116 patients in a phase Ib/II study. Blood (ASH Annual Meeting Abstracts). 2012;120:189.
  • Advani RH, Buggy JJ, Sharman JP, Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol 2013;31:88–94.
  • O'Brien S, Burger JA, Coutre SE The Btk Inhibitor PCI-32765 is highly active and tolerable in patients with poor-risk CLL: interim results from a phase Ib/II study. Ann Oncol 2011;22(Suppl. 4):iv123–iv124.
  • O'Brien S, Burger JA, Blum KA The Bruton'styrosine kinase (BTK) inhibitor PCI-32765 induces durable responses in relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): follow-up of a phase Ib/II study. Blood 2011;118:449 (Abstract 983).
  • Burger JA, Keating MJ, Wierda WG The Btkinhibitor ibrutinib (PCI-32765) in combination with rituximab is well tolerated and displays profound activity in high-risk chronic lymphocytic leukemia (CLL) patients. Blood (ASH Annual Meeting Abstracts) 2012;120:187.
  • Farooqui M, Aue G, Valdez J, Rapid decrease in overall tumor burden on ibrutinib (PCI-32765) in CLL despite transient increase in ALC indicates a significant degree of treatment induced cell death. Blood (ASH Annual MeetingAbstracts) 2012;120:2899.
  • Ciraolo E, Perino A, Hirsch E. Measuring PI3K lipid kinase activity. Methods Mol Biol 2012;795:55–67.
  • Macias-Perez IM, Flinn IW. GS-1101: a delta-specific PI3K inhibitor in chronic lymphocytic leukemia. Cur Hematol Malig Rep 2012 Nov 2. [Epub ahead of print]
  • Okkenhaug K, Vanhaesebroeck B. PI3K in lymphocyte development, differentiation and activation. Nat Rev Immunol 2003;3:317–330.
  • Hoellenriegel J, Meadows SA, Wierda WG Phosphoinositide 3’-Kinase (PI3K) delta inhibition with CAL-101 blocks B-cell receptor (BCR) signaling and the prosurvival actions of nurslike cells (NLC), in chronic lymphocytic leukemia. American Society of Hematology Annual Meeting Abstracts. Blood 2010;116:27 (Abstract 48).
  • Herman SE, Gordon AL, Wagner AJ Phosphatidylinositol 3-kinase-delta inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood 2010;116:2078–2088.
  • Macias-Perez IM, Flinn IW. GS-1101: a delta-specific PI3K inhibitor in chronic lymphocytic leukemia. Curr Hematol Malig Rep 2013;8:22–27.
  • Dienstmann R, Rodon J, Markman B, Tabernero J. Recentdevelopments in anti-cancer agents targeting PI3K, Akt and mTORC1/2. Recent Pat Anticancer Drug Discov 2011;6:210–236.
  • Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 2006;7:606–619.
  • Castillo JJ, Furman M, Winer ES. CAL-101: a phosphatidylinositol-3-kinase p110-delta inhibitor for the treatment of lymphoid malignancies. Expert Opin Investig Drugs 2012;21:15–22.
  • Meadows SA, Vega F, Kashishian A, PI3Kδ inhibitor, GS- 1101(CAL-101), attenuates pathway signaling, induces apoptosis, and overcomes signals from the microenvironment in cellular models of Hodgkin lymphoma. Blood 2012;119:1897–900.
  • Hoellenriegel J, Meadows SA, Sivina M, The phosphoinositide 3’- kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood 2011;118; 3603–3612.
  • Lannutti BJ, Meadows SA, Herman SE, CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood 2011;117:591–594.
  • Burger JA. Inhibiting B-cell receptor signaling pathways in chronic lymphocytic leukemia. Curr Hematol Malig Rep 2012;7:26–33.
  • Fiorcari S, Brown WS, McIntyre BW, The PI3 kinase {delta} inhibitor, CAL-101 (GS-1101), inhibits chronic lymphocytic leukemia (CLL) cell survival in endothelial and marrow stromal cell co-cultures. Blood (ASH Annual Meeting Abstracts) 2011;118: 771 (Abstract 1769).
  • Furman RR, Byrd JC, Brown JR, CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3-kinase P110{delta}, demonstrates clinical activity and pharmacodynamic effects in patients with relapsed or refractory chronic lymphocytic leukemia. Blood (ASH Annual Meeting Abstracts) 2010;116:31 (Abstract 55).
  • Furman RR, Byrd JC, Flinn IW, Interim results from a phase I study of CAL-101, a selective oral inhibitor of phosphatidylinositol 3-kinase p110d isoform, in patients with relapsed or refractory hematologic malignancies. J Clin Oncol 2010;28:15, (suppl) Abstract 3032.
  • de Vos S, Schreeder MT, Flinn IW, A phase 1 study of the selective phosphatidylinositol 3-kinase-delta (PI3K{delta}) inhibitor, Cal-101 (GS-1101), in combination with rituximab and/or bendamustine in patients with previously treated, indolent non-Hodgkin lymphoma (iNHL). Blood (ASH Annual Meeting Abstracts) 2011;118: 1160 (Abstract 2699).
  • Coutre SE, Leonard JP, Furman RR, Combinations of the selective phosphatidylinositol 3-kinase-delta (PI3Kdelta) inhibitor GS–1101 (CAL-101) with rituximab and/or bendamustine are tolerable and highly active in patients with relapsed or refractory chronic lymphocytic leukemia (CLL): results from a phase I study. Blood (ASH Annual Meeting Abstracts) 2012;120:191.
  • Fowler NH, de Vos S, Schreeder MT, Combinations of the phosphatidylinositol 3-kinase-delta (PI3K) inhibitor Gs-1101 (CAL-101) with rituximab and/or bendamustine are tolerable and highly active in previously treated, indolent Non-Hodgkin lymphoma: Results from a phase I study Blood (ASH Annual Meeting Abstracts) 2012;120: 3645.
  • Friedman DR, Lanasa MC, Danielle M, Comparison of the PI3K- inhibitors TGR1202 and GS-1101 in inducing cytotoxicity and inhibiting phosphorylation of Akt in CLL cells in vitro. Blood (ASH Annual Meeting Abstracts) 2012;120:3914.
  • Burke RT, Clarke A, Sarah A, Potential therapeutic strategy for chronic lymphocytic leukemia by combining GS-1101, a PI3 kinase delta (PI3K) inhibitor and a novel highly selective spleen tyrosine kinase (Syk) inhibitor, GS-9973 Blood (ASH Annual Meeting Abstracts), 2012;120: 3876.
  • Mócsai A, Ruland J, Tybulewicz VL. The SYK tyrosine kinase: a crucial player in diverse biological functions. Nat Rev Immunol 2010;10:387–402.
  • Geahlen RL. Syk and pTyr'd: signaling through the B-cell antigen receptor. Biochim Biophys Acta 2009;1793:1115–1127.
  • Gauld SB, Dal Porto JM, Cambier JC. B cell antigen receptor signaling: roles in cell development and disease. Science 2002;296:1641–1642.
  • Baudot AD, Jeandel PY, Mouska X, The tyrosine kinase Syk regulates the survival of chronic lymphocytic leukemia B-cells through PKCdelta and proteasome-dependent regulation of Mcl-1 expression. Oncogene 2009;28:3261–3273.
  • Buchner M, Fuchs S, Prinz G, Spleen tyrosine kinase is overexpressed and represents a potential therapeutic target in chronic lymphocytic leukemia. Cancer Res 2009;69:5424–5432.
  • Davids MS, Brown JR. Targeting the B-cell receptor pathway in chronic lymphocytic leukemia. Leuk Lymphoma 2012;53:2362–2370.
  • Zhang Y, Parmentier J, Lai Z, , Spleen tyrosine kinase inhibitor fostamatinib blocks B-cell receptor signaling and reduces viability of BCR subtype diffuse large B-cell lymphoma. Blood (ASH Annual Meeting Abstracts) 2012;120:3720.
  • Hoellenriegel J, Coffey GP, Sinha U, Selective, novel spleen tyrosine kinase (Syk) inhibitors suppress chronic lymphocytic leukemia B-cell activation and migration. Leukemia 2012;26:1576–1583.
  • Suljagic M, Longo PG, Bennardo S, The Syk inhibitor fostamatinib disodium (R788) inhibits tumor growth in the E{micro}- TCL1 transgenic mouse model of CLL by blocking antigen-dependent B-cell receptor signaling. Blood 2010;116:4894–4905.
  • Herman SEM, Barr PM, McAuley EM, Fostamatinib inhibits BCR signaling, and reduces tumor cell activation and proliferation in patients with relapsed refractory chronic lymphocytic leukemia. Blood (ASH Annual Meeting Abstracts) 2012;120:2882.
  • Gobessi S, Laurenti L, Longo PG, Inhibition of constitutive and BCR-induced Syk activation downregulates Mcl-1 and induces apoptosis in chronic lymphocytic leukemia B-cells. Leukemia 2009;23:686–697.
  • Quiroga MP, Balakrishnan K, Kurtova AV, B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406. Blood 2009;114:1029–1037.
  • Friedberg JW, Sharman J, Sweetenham J, Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood 2010;115:2578–2585.
  • Niiro H, Clark EA. Regulation of B-cell fate by antigen-receptor signals. Nat Rev Immunol 2002;2:945–956.
  • Contri A, Brunati AM, Trentin L, Chronic lymphocytic leukemia B-cells contain anomalous Lyn tyrosine kinase, a putative contribution to defective apoptosis. J Clin Invest 2005;115:369–378.
  • Gora-Tybor J, Robak T. Targeted drugs in chronic myeloid leukemia. Curr Med Chem 2008;15:3036–3051.
  • Veldurthy A, Patz M, Hagist S, The kinase inhibitor dasatinib induces apoptosis in chronic lymphocytic leukemia cells in vitro with preference for a subgroup of patients with unmutated IgVH genes. Blood 2008;112:1443–1452.
  • ten Hacken E, Scielzo C, Betilaccio MTS, et al., Targeting the LYN/HS1 signaling axis in chronic lymphocytic leukemia. Blood (ASH Annual Meeting Abstracts) 2012;120:928.
  • Aguillon RA, Llanos CA, Suarez CJ, Dasatinib induces apoptosis in chronic lymphocytic leukemia and enhances the activity of rituximab and fludarabine. Blood (ASH Annual Meeting Abstracts) 2007;110:339a (Abstract 1116).
  • Harr MW, Caimi PF, McColl K, The tyrosine kinase inhibitor dasatinib enhances glucocorticoid-induced apoptosis and sensitizes chronic lymphocytic leukemia cells to dexamethasone. Blood (ASH Annual Meeting Abstracts) 2009;114: 4811.
  • Amrein L, Hernandez TA, Ferrario C, Dasatinib sensitizes primary chronic lymphocytic leukaemia lymphocytes to chlorambucil and fludarabine in vitro. Br J Haematol 2008;143:698–706.
  • Amrein PC, Attar EC, Takvorian T, Phase II study of dasatinib in relapsed or refractory chronic lymphocytic leukemia. Clin Cancer Res 2011;17:2977–2986.
  • Kater AP, Spiering M, Liu RD, The broad kinase inhibitor dasatinib in combination with fludarabine in patients with refractory chronic lymphocytic leukemia: a multicenter phase 2 study. Blood (ASH Annual Meeting Abstracts) 2012;120:1798.
  • Santos FP, Kantarjian H, Cortes J, Quintas-Cardama A. Bafetinib, a dual Bcr-Abl/Lyn tyrosine kinase inhibitor for the potential treatment of leukemia. Cur Opin Investig Drugs 2010;11:1450–1465.
  • Kimura S, Naito H, Segawa H, NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia. Blood 2005;106: 3948–3954.
  • Niwa T, Asaki T, Kiura S. NS-187 (INNO-406), a Bcr-Abl/Lyn dual tyrosine kinase inhibitor. Anal Chem Insights 2007;2:93–106.
  • Kadia T, Delioukina ML, Kantarjian HM, A pilot phase II study of the Lyn kinase inhibitor bafetinib in patients with relapsed or refractory B-cell chronic lymphocytic leukemia. Blood (ASH Annual Meeting Abstracts) 2011;118: 2858.
  • Robak T. Inhibitors of B-Cell receptor signaling for the treatment of chronic lymphocytic leukemia. J Leuk 2013;1:e101. doi:10.4172 /jlu.1000e101

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