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A review on the potential of Bruton’s tyrosine kinase (Btk) inhibitor – Ibrutinib for treatment of Multiple Myeloma (MM)

Sze-Ting Bong, Lydia Ngiik-Shiew Law, Jodi Woan-Fei Law Abstract - 1589 PDF - 40


Multiple myeloma (MM) is characterized by the over-production of monoclonal plasma cells that eventually become malignant in the bone marrow. MM remains as an incurable cancer, but it can be treated through chemotherapy. Nonetheless, research on novel therapies for effective treatment of MM is ongoing and in this case the involvement of Bruton’s tyrosine kinase (Btk) in B-cell malignancies has made it one of the new therapeutic targets. In MM patients, it has been reported that the expression of Btk was elevated and this could potentially contribute to chemoresistance indirectly via enhancement of cell proliferation and survival. Ibrutinib is a highly selective irreversible Btk inhibitor commonly used as treatment for B-cell malignancies such as Mantle Cell Lymphoma (MCL) and Chronic Lymphocytic Leukemia (CLL). With reference to the potential involvement of Btk in MM and current treatment of MCL and CLL using ibrutinib, researchers have begun to examine the effect of ibrutinib treatment on MM. This review provides information on the association of MM and Btk in conjunction with the treatment using ibrutinib. To date, clinical trials of ibrutinib as therapeutic alternative for MM have produced promising results, particularly as combination therapy with other agents such as dexamethasone and carfilzomib. However, there is limited evidence on the Btk mechanisms involved in MM, hence, it is important to further investigate the Btk oncogenic signalling pathway(s) in MM cells in order to establish successful and improved treatment of MM.

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Bam R, Ling W, Khan S, et al. Role of Bruton's tyrosine kinase in myeloma cell migration and induction of bone disease. Am J Hematol 2013; 88(6): 463-471.

Middela S and Kanse P. Nonsecretory multiple myeloma. Indian J Orthop 2009; 43(4): 408-411.

Palumbo A and Anderson K. Multiple myeloma. N Engl J Med 2011; 364(11): 1046-1060.

Mehta GR, Suhail F, Haddad, RY, et al. Multiple myeloma. Disease-a-month: DM 2014; 60(10): 483-488.

Dong H, Chen L, Chen X, et al. Dysregulation of unfolded protein response partially underlies proapoptotic activity of bortezomib in multiple myeloma cells. Leukemia & Lrymphoma 2009; 50(6): 974-984.

Rushworth SA, Bowles KM, Barrera LN, et al. BTK inhibitor ibrutinib is cytotoxic to myeloma and potently enhances bortezomib and lenalidomide activities through NF-κB. Cell Signal 2013; 25(1): 106-112.

Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 2010; 116(5): 679-686.

Suzuki K. Current therapeutic strategy for multiple myeloma. Jap J Clin Oncol 2013; 43(2): 116-124.

American Cancer Society. Multiple Myeloma overview. 2014. Available on

Raab, MS, Podar, K, Breitkreutz, I, et al. Multiple myeloma. Lancet 2009; 374(9686): 324-339.

Munshi, NC and Anderson, KC. New strategies in the treatment of multiple myeloma. Clin Cancer Res 2013; 19(13): 3337-3344.

Tai Y-T, Chang BY, Kong S-Y, et al. Bruton tyrosine kinase inhibition is a novel therapeutic strategy targeting tumor in the bone marrow microenvironment in multiple myeloma. Blood 2012; 120(9): 1877-1887.

Burger JA and Buggy JJ. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765). Leuk Lymphoma 2013; 54(11): 2385-2391.

Burger JA and Chiorazzi N. B cell receptor signaling in chronic lymphocytic leukemia. Trends Immunol 2013; 34(12): 592-601.

Tsukada S, Saffran DC, Rawlings DJ, et al. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell 1993; 72(2): 279-290.

Mano H. Tec family of protein-tyrosine kinases: An overview of their structure and function. Cytokine Growth Factor Rev 1999; 10(3-4): 267-280.

Mohamed AJ, Yu L, Bäckesjö CM, et al. Bruton’s tyrosine kinase (Btk): Function, regulation, and transformation with special emphasis on the PH domain. Immunol Rev 2009; 228(1): 58-73.

Bruton OC. Agammaglobulinemia. Pediatrics 1952; 9(6): 722-728.

Camcıoğlu Y. Bruton’s Disease. In: Immunopathology and Immunomodulation. K Metodiev, Croatia: InTech; 2015: 217-243.

Smith C. From identification of the BTK kinase to effective management of leukemia. Oncogene 2017; 36(15): 2045-2053.

Hagemann TL, Chen Y, Rosen FS, et al. Genomic organization of the Btk gene and exon scanning for mutations in patients with X-linked agammaglobulinemia. Hum Mol Genet 1994; 3(10): 1743-1749.

Smith CE, Bäckesjö C-M, Berglöf A, et al. X-linked agammaglobulinemia: lack of mature B lineage cells caused by mutations in the Btk kinase. In: Springer Semin Immunopathol, Springer; 1998: 369-381.

Li T, Tsukada S, Satterthwaite A, et al. Activation of Bruton's tyrosine kinase (BTK) by a point mutation in its pleckstrin homology (PH) domain. Immunity 1995; 2(5): 451-460.

Salim K, Bottomley MJ, Querfurth E, et al. Distinct specificity in the recognition of phosphoinositides by the pleckstrin homology domains of dynamin and Bruton's tyrosine kinase. EMBO J 1996; 15(22): 6241-6250.

Rawlings DJ, Saffran DC, Tsukada S, et al. Mutation of unique region of Bruton's tyrosine kinase in immunodeficient XID mice. Science 1993; 261(5119): 358-361.

Mohamed A, Nore B, Christensson B, et al. Signalling of Bruton's tyrosine kinase, Btk. Scand J Immunol 1999; 49(2): 113-118.

Hyvönen M and Saraste M. Structure of the PH domain and Btk motif from Bruton's tyrosine kinase: Molecular explanations for X-linked agammaglobulinaemia. EMBO J 1997; 16(12): 3396-3404.

Yao L, Kawakami Y, and Kawakami T. The pleckstrin homology domain of Bruton tyrosine kinase interacts with protein kinase C. Proc Natl Acad Sci 1994; 91(19): 9175-9179.

Yao L, Suzuki H, Ozawa K, et al. Interactions between protein kinase C and pleckstrin homology domains Inhibition by phosphatidylinositol 4, 5-bisphosphate and phorbol 12-myristate 13-acetate. J Biol Chem 1997; 272(20): 13033-13039.

Tsukada S, Simon MI, Witte ON, et al. Binding of beta gamma subunits of heterotrimeric G proteins to the PH domain of Bruton tyrosine kinase. Proc Natl Acad Sci 1994; 91(23): 11256-11260.

Yang W and Desiderio S. BAP-135, a target for Bruton’s tyrosine kinase in response to B cell receptor engagement. Proc Natl Acad Sci 1997; 94(2): 604-609.

Vassilev A, Ozer Z, Navara C, et al. Bruton’s tyrosine kinase as an inhibitor of the Fas/CD95 death-inducing signaling complex. J Biol Chem 1999; 274(3): 1646-1656.

Vihinen M, Nilsson L, and Smith CE. Tec homology (TH) adjacent to the PH domain. FEBS Lett 1994; 350(2-3): 263-265.

Vihinen M, Nore BF, Mattsson PT, et al. Missense mutations affecting a conserved cysteine pair in the TH domain of Btk. FEBS Lett 1997; 413(2): 205-210.

Hansson H, Okoh MP, Smith CE, et al. Intermolecular interactions between the SH3 domain and the prolinerich TH region of Bruton's tyrosine kinase. FEBS Lett 2001; 489(1): 67-70.

Okoh MP and Vihinen M. Interaction between Btk TH and SH3 domain. Biopolymers 2002; 63(5): 325-334.

Gustafsson MO, Hussain A, Mohammad DK, et al. Regulation of nucleocytoplasmic shuttling of Bruton's tyrosine kinase (Btk) through a novel SH3-dependent interaction with ankyrin repeat domain 54 (ANKRD54). Mol Cell Biol 2012; 32(13): 2440-2453.

Tzeng SR, Pai MT, Lung FDT, et al. Stability and peptide binding specificity of Btk SH2 domain: Molecular basis for X-linked agammaglobulinemia. Protein Sci 2000; 9(12): 2377-2385.

Baba Y, Hashimoto S, Matsushita M, et al. BLNK mediates Syk-dependent Btk activation. Proc Natl Acad Sci 2001; 98(5): 2582-2586.

Hashimoto S, Iwamatsu A, Ishiai M, et al. Identification of the SH2 domain binding protein of Bruton’s tyrosine kinase as BLNK—functional significance of Btk-SH2 domain in B-cell antigen receptor-coupled calcium signaling. Blood 1999; 94(7): 2357-2364.

Vetrie D, Vořechovský I, Sideras P, et al. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature 1993; 361(6409): 226-233.

Dinh M, Grunberger D, Ho H, et al. Activation mechanism and steady state kinetics of Bruton's tyrosine kinase. J Biol Chem 2007; 282(12): 8768-8776.

Mahajan S, Fargnoli J, Burkhardt AL, et al. Src family protein tyrosine kinases induce autoactivation of Bruton's tyrosine kinase. Mol Cell Biol 1995; 15(10): 5304-5311.

Márquez JA, Smith CE, Petoukhov MV, et al. Conformation of full length Bruton tyrosine kinase (Btk) from synchrotron X-ray solution scattering. EMBO J 2003; 22(18): 4616-4624.

Xu W, Harrison SC, and Eck MJ. Three-dimensional structure of the tyrosine kinase c-Src. Nature 1997; 385(6617): 595-602.

Park H, Wahl MI, Afar DE, et al. Regulation of Btk function by a major autophosphorylation site within the SH3 domain. Immunity 1996; 4(5): 515-525.

Lowry WE, Huang J, Lei M, et al. Role of the PHTH module in protein substrate recognition by Bruton's agammaglobulinemia tyrosine kinase. J Biol Chem 2001; 276(48): 45276-45281.

Janeway CA, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. Vol. 7. 2001, London: Current Biology

Khan WN. Regulation of B lymphocyte development and activation by Bruton's tyrosine kinase. Immunol Res 2001; 23(2-3): 147-156.

Rawlings DJ, Scharenberg AM, Park H, et al. Activation of BTK by a phosphorylation mechanism initiated by SRC family kinases. Science 1996; 271(5250): 822-825.

Monroe JG. ITAM-mediated tonic signalling through pre-BCR and BCR complexes. Nature Rev Immuno 2006; 6(4): 283-294.

Li Z, Wahl MI, Eguinoa A, et al. Phosphatidylinositol 3-kinase-γ activates Bruton’s tyrosine kinase in concert with Src family kinases. Proc Natl Acad Sci 1997; 94(25): 13820-13825.

Brown JR. Ibrutinib (PCI-32765), the first BTK (Bruton’s tyrosine kinase) inhibitor in clinical trials. Curr Hematol Malig R 2013; 8(1): 1-6.

Kurosaki T and Tsukada S. BLNK: Connecting Syk and Btk to calcium signals. Immunity 2000; 12(1): 1-5.

Yu L, Mohamed AJ, Simonson OE, et al. Proteasome-dependent autoregulation of Bruton tyrosine kinase (Btk) promoter via NF-κB. Blood 2008; 111(9): 4617-4626.

Shinners NP, Carlesso G, Castro I, et al. Bruton’s tyrosine kinase mediates NF-κB activation and B cell survival by B cell-activating factor receptor of the TNF-R family. J Immunol 2007; 179(6): 3872-3880.

Cameron F and Sanford M. Ibrutinib: First global approval. Drugs 2014; 74(2): 263-271.

Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. New Engl J Med 2013; 369(6): 507-516.

Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. New Engl J Med 2013; 369(1): 32-42.

Pan Z, Scheerens H, Li SJ, et al. Discovery of selective irreversible inhibitors for Bruton’s tyrosine kinase. Chem Med Chem 2007; 2(1): 58-61.

Lou Y, Owens TD, Kuglstatter A, et al. Bruton’s tyrosine kinase inhibitors: Approaches to potent and selective inhibition, preclinical and clinical evaluation for inflammatory diseases and B cell malignancies. J Med Chem 2012; 55(10): 4539-4550.

Huse M and Kuriyan J. The conformational plasticity of protein kinases. Cell 2002; 109(3): 275-282.

Cohen MS, Zhang C, Shokat KM, et al. Structural bioinformatics-based design of selective, irreversible kinase inhibitors. Science 2005; 308(5726): 1318-1321.

Honigberg LA, Smith AM, Sirisawad M, et al. 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 2010; 107(29): 13075-13080.

de Weers M, Verschuren MC, Kraakman ME, et al. The Bruton's tyrosine kinase gene is expressed throughout B cell differentiation, from early precursor B cell stages preceding immunoglobulin gene rearrangement up to mature B cell stages. Eur J Immunol 1993; 23(12): 3109-3114.

Smith C, Baskin B, Humire-Greiff P, et al. Expression of Bruton's agammaglobulinemia tyrosine kinase gene, BTK, is selectively down-regulated in T lymphocytes and plasma cells. J Immunol 1994; 152(2): 557-565.

Bajpai UD, Zhang K, Teutsch M, et al. Bruton's tyrosine kinase links the B cell receptor to nuclear factor κB activation. J Exp Med 2000; 191(10): 1735-1744.

Siebenlist U, Brown K, and Claudio E. Control of lymphocyte development by nuclear factor-κB. Nature Revi Immuno 2005; 5(6): 435-445.

Murray MY, Zaitseva L, Auger MJ, et al. Ibrutinib inhibits BTK-driven NF-κB p65 activity to overcome bortezomib-resistance in multiple myeloma. Cell Cycle 2015; 14(14): 2367-2375.

Liu Y, Dong Y, Jiang QL, et al. Bruton's tyrosine kinase: potential target in human multiple myeloma. Leuk Lymphoma 2014; 55(1): 177-181.

Shinohara M, Koga T, Okamoto K, et al. Tyrosine kinases Btk and Tec regulate osteoclast differentiation by linking RANK and ITAM signals. Cell 2008; 132(5): 794-806.

Lee SH, Kim T, Jeong D, et al. The tec family tyrosine kinase Btk Regulates RANKL-induced osteoclast maturation. J Biol Chem 2008; 283(17): 11526-11534.

Bam R, Venkateshaiah S, Khan S, et al. Role of Bruton’s tyrosine kinase (BTK) in growth and metastasis of INA6 myeloma cells. Blood Cancer J 2014; 4(8): e234.

Vij R, Huff CA, Bensinger WI, et al. Ibrutinib, single agent or in combination with dexamethasone, in patients with relapsed or relapsed/refractory multiple myeloma (MM): Preliminary phase 2 results. Blood 2014; 124: 31.

Chari A, Larson S, Holkova B, et al. Phase 1 trial of ibrutinib and carfilzomib combination therapy for relapsed or relapsed and refractory multiple myeloma. Leuk Lymphoma 2018; 59(11): 2588-2594.

Tai YT and Anderson KC. Bruton's tyrosine kinase: oncotarget in myeloma. Oncotarget 2012; 3(9): 913-914.

Naymagon L and Abdul-Hay M. Novel agents in the treatment of multiple myeloma: a review about the future. J Hematol Oncol 2016; 9(1): 52.

Ping L, Ding N, Shi Y, et al. The Bruton's tyrosine kinase inhibitor ibrutinib exerts immunomodulatory effects through regulation of tumor-infiltrating macrophages. Oncotarget 2017; 8(24): 39218-39229.


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