Bruton’s Tyrosine Kinase (BTK)-Inhibitors in Cancer Therapeutics
DOI:
https://doi.org/10.12974/2309-6160.2021.05.1Keywords:
BTK, Inhibition, CLL, Ibrutinib, Cell.Abstract
While continuous global efforts are directed towards finding a conclusive medication for cancer treatment, any gold standard drug product or process is yet to be achieved. Although, many promising compounds were identified over the years to fight cancer progression, most of them still remain restricted within clinical trial phases. Among several identified pathways for modulating cancer progression, Bruton’s tyrosine kinase (BTK) pathway inhibition has shown a greater potential. BTK regulates various aspects of B-cell lineages including proliferation, activation, differentiation, and survival. BTK is also responsible for multiple cellular signaling pathways, of which, FcR signaling cascade and B- cell receptor signaling are notable. Interestingly, BTK expression was reported to be excessively high in all the areas where B-cell mediated malignancies occur. Vivid involvement of BTK in several autoimmune diseases also rationally support the realization that BTK inhibition could be a conclusive therapeutic approach for cancer. In this short communication, we discuss the potential of BTK inhibitors in cancer therapeutics, considering the most recent literature.
References
Manning, G., Whyte, D. B., Martinez, R., Hunter, T., & Sudarsanam, S. (2002). The protein kinase complement of the human genome. Science (New York, N.Y.), 298(5600), 1912–1934. https://doi.org/10.1126/science.1075762
Berg JM, Tymoczko JL, Stryer L. Biochemistry. 5th edition. New York: W H Freeman; 2002. Section 10.4, Covalent Modification Is a Means of Regulating Enzyme Activity. Available from: https://www.ncbi.nlm.nih.gov/books/NBK22399/
Gross, S., Rahal, R., Stransky, N., Lengauer, C., & Hoeflich, K. P. (2015). Targeting cancer with kinase inhibitors. The Journal of clinical investigation, 125(5), 1780–1789. https://doi.org/10.1172/JCI76094
Buggy, J. J., & Elias, L. (2012). Bruton tyrosine kinase (BTK) and its role in B-cell malignancy. International reviews of immunology, 31(2), 119–132. https://doi.org/10.3109/08830185.2012.664797
Hendriks, R. W., Yuvaraj, S., & Kil, L. P. (2014). Targeting Bruton's tyrosine kinase in B cell malignancies. Nature reviews. Cancer, 14(4), 219–232. https://doi.org/10.1038/nrc3702
Pal Singh, S., Dammeijer, F., & Hendriks, R. W. (2018). Role of Bruton's tyrosine kinase in B cells and malignancies. Molecular cancer, 17(1), 57. https://doi.org/10.1186/s12943-018-0779-z
Shinohara, M., Koga, T., Okamoto, K., Sakaguchi, S., Arai, K., Yasuda, H., Takai, T., Kodama, T., Morio, T., Geha, R. S., Kitamura, D., Kurosaki, T., Ellmeier, W., & Takayanagi, H. (2008). Tyrosine kinases Btk and Tec regulate osteoclast differentiation by linking RANK and ITAM signals. Cell, 132(5), 794–806. https://doi.org/10.1016/j.cell.2007.12.037
Oda, A., Ikeda, Y., Ochs, H. D., Druker, B. J., Ozaki, K., Handa, M., Ariga, T., Sakiyama, Y., Witte, O. N., & Wahl, M. I. (2000). Rapid tyrosine phosphorylation and activation of Bruton's tyrosine/Tec kinases in platelets induced by collagen binding or CD32 cross-linking. Blood, 95(5), 1663–1670
Ito, M., Shichita, T., Okada, M., Komine, R., Noguchi, Y., Yoshimura, A., & Morita, R. (2015). Bruton's tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury. Nature communications, 6, 7360. https://doi.org/10.1038/ncomms8360
Geier, C. B., Sauerwein, K., Leiss-Piller, A., Zmek, I., Fischer, M. B., Eibl, M. M., & Wolf, H. M. (2018). Hypomorphic Mutations in the BCR Signalosome Lead to Selective Immunoglobulin M Deficiency and Impaired B-cell Homeostasis. Frontiers in immunology, 9, 2984. https://doi.org/10.3389/fimmu.2018.02984
Muta, T., Kurosaki, T., Misulovin, Z., Sanchez, M., Nussenzweig, M. C., & Ravetch, J. V. (1994). A 13-amino-acid motif in the cytoplasmic domain of Fc gamma RIIB modulates B-cell receptor signalling. Nature, 368(6466), 70–73. https://doi.org/10.1038/368070a0
Bolland, S., & Ravetch, J. V. (1999). Inhibitory pathways triggered by ITIM-containing receptors. Advances in immunology, 72, 149–177. https://doi.org/10.1016/s0065-2776(08)60019-x
Ono, M., Bolland, S., Tempst, P., & Ravetch, J. V. (1996). Role of the inositol phosphatase SHIP in negative regulation of the immune system by the receptor Fc(gamma)RIIB. Nature, 383(6597), 263–266. https://doi.org/10.1038/383263a0
Kang, S. W., Wahl, M. I., Chu, J., Kitaura, J., Kawakami, Y., Kato, R. M., Tabuchi, R., Tarakhovsky, A., Kawakami, T., Turck, C. W., Witte, O. N., & Rawlings, D. J. (2001). PKCbeta modulates antigen receptor signaling via regulation of Btk membrane localization. The EMBO journal, 20(20), 5692–5702. https://doi.org/10.1093/emboj/20.20.5692
Liu, W., Quinto, I., Chen, X., Palmieri, C., Rabin, R. L., Schwartz, O. M., Nelson, D. L., & Scala, G. (2001). Direct inhibition of Bruton's tyrosine kinase by IBtk, a Btk-binding protein. Nature immunology, 2(10), 939–946. https://doi.org/10.1038/ni1001-939
Bottoni, A., Rizzotto, L., Lai, T. H., Liu, C., Smith, L. L., Mantel, R., Reiff, S., El-Gamal, D., Larkin, K., Johnson, A. J., Lapalombella, R., Lehman, A., Plunkett, W., Byrd, J. C., Blachly, J. S., Woyach, J. A., & Sampath, D. (2016). Targeting BTK through microRNA in chronic lymphocytic leukemia. Blood, 128(26), 3101–3112. https://doi.org/10.1182/blood-2016-07-727750
Yu, L., Mohamed, A. J., Simonson, O. E., Vargas, L., Blomberg, K. E., Björkstrand, B., Arteaga, H. J., Nore, B. F., & Smith, C. I. (2008). Proteasome-dependent autoregulation of Bruton tyrosine kinase (Btk) promoter via NF-kappaB. Blood, 111(9), 4617–4626. https://doi.org/10.1182/blood-2007-10-121137
Pan, Z., Scheerens, H., Li, S. J., Schultz, B. E., Sprengeler, P. A., Burrill, L. C., Mendonca, R. V., Sweeney, M. D., Scott, K. C., Grothaus, P. G., Jeffery, D. A., Spoerke, J. M., Honigberg, L. A., Young, P. R., Dalrymple, S. A., & Palmer, J. T. (2007). Discovery of selective irreversible inhibitors for Bruton's tyrosine kinase. ChemMedChem, 2(1), 58–61. https://doi.org/10.1002/cmdc.200600221
Honigberg, L. A., Smith, A. M., Sirisawad, M., Verner, E., Loury, D., Chang, B., Li, S., Pan, Z., Thamm, D. H., Miller, R. A., & Buggy, J. J. (2010). The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proceedings of the National Academy of Sciences of the United States of America, 107(29), 13075–13080. https://doi.org/10.1073/pnas.1004594107
Harrington, B. K., Gardner, H. L., Izumi, R., Hamdy, A., Rothbaum, W., Coombes, K. R., Covey, T., Kaptein, A., Gulrajani, M., Van Lith, B., Krejsa, C., Coss, C. C., Russell, D. S., Zhang, X., Urie, B. K., London, C. A., Byrd, J. C., Johnson, A. J., & Kisseberth, W. C. (2016). Preclinical Evaluation of the Novel BTK Inhibitor Acalabrutinib in Canine Models of B-Cell Non-Hodgkin Lymphoma. PloS one, 11(7), e0159607. https://doi.org/10.1371/journal.pone.0159607
Advani, R. H., Buggy, J. J., Sharman, J. P., Smith, S. M., Boyd, T. E., Grant, B., Kolibaba, K. S., Furman, R. R., Rodriguez, S., Chang, B. Y., Sukbuntherng, J., Izumi, R., Hamdy, A., Hedrick, E., & Fowler, N. H. (2013). Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765)
has significant activity in patients with relapsed/refractory B-cell malignancies. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 31(1), 88–94. https://doi.org/10.1200/JCO.2012.42.7906
Byrd, J. C., Furman, R. R., Coutre, S. E., Flinn, I. W., Burger, J. A., Blum, K. A., Grant, B., Sharman, J. P., Coleman, M., Wierda, W. G., Jones, J. A., Zhao, W., Heerema, N. A., Johnson, A. J., Sukbuntherng, J., Chang, B. Y., Clow, F., Hedrick, E., Buggy, J. J., James, D. F., … O'Brien, S. (2013). Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. The New England journal of medicine, 369(1), 32–42. https://doi.org/10.1056/NEJMoa1215637
Wang, M. L., Rule, S., Martin, P., Goy, A., Auer, R., Kahl, B. S., Jurczak, W., Advani, R. H., Romaguera, J. E., Williams, M. E., Barrientos, J. C., Chmielowska, E., Radford, J., Stilgenbauer, S., Dreyling, M., Jedrzejczak, W. W., Johnson, P., Spurgeon, S. E., Li, L., Zhang, L., … Blum, K. A. (2013). Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. The New England journal of medicine, 369(6), 507–516. https://doi.org/10.1056/NEJMoa1306220
Grommes, C., Pastore, A., Palaskas, N., Tang, S. S., Campos, C., Schartz, D., Codega, P., Nichol, D., Clark, O., Hsieh, W. Y., Rohle, D., Rosenblum, M., Viale, A., Tabar, V. S., Brennan, C. W., Gavrilovic, I. T., Kaley, T. J., Nolan, C. P., Omuro, A., Pentsova, E., … Mellinghoff, I. K. (2017). Ibrutinib Unmasks Critical Role of Bruton Tyrosine Kinase in Primary CNS Lymphoma. Cancer discovery, 7(9), 1018–1029. https://doi.org/10.1158/2159-8290.CD-17-0613
Burger, J. A., Barr, P. M., Robak, T., Owen, C., Ghia, P., Tedeschi, A., Bairey, O., Hillmen, P., Coutre, S. E., Devereux, S., Grosicki, S., McCarthy, H., Simpson, D., Offner, F., Moreno, C., Dai, S., Lal, I., Dean, J. P., & Kipps, T. J. (2020). Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia, 34(3), 787–798. https://doi.org/10.1038/s41375-019-0602-x
Herman, S. E., Gordon, A. L., Hertlein, E., Ramanunni, A., Zhang, X., Jaglowski, S., Flynn, J., Jones, J., Blum, K. A., Buggy, J. J., Hamdy, A., Johnson, A. J., & Byrd, J. C. (2011). Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood, 117(23), 6287–6296. https://doi.org/10.1182/blood-2011-01-328484
de Gorter, D. J., Beuling, E. A., Kersseboom, R., Middendorp, S., van Gils, J. M., Hendriks, R. W., Pals, S. T., & Spaargaren, M. (2007). Bruton's tyrosine kinase and phospholipase Cgamma2 mediate chemokine-controlled B cell migration and homing. Immunity, 26(1), 93–104. https://doi.org/10.1016/j.immuni.2006.11.012
de Rooij, M. F., Kuil, A., Geest, C. R., Eldering, E., Chang, B. Y., Buggy, J. J., Pals, S. T., & Spaargaren, M. (2012). The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood, 119(11), 2590–2594. https://doi.org/10.1182/blood-2011-11-390989
Wen, T., Wang, J., Shi, Y., Qian, H., & Liu, P. (2021). Inhibitors targeting Bruton's tyrosine kinase in cancers: drug development advances. Leukemia, 35(2), 312–332. https://doi.org/10.1038/s41375-020-01072-6
Burger, J. A., & Wiestner, A. (2018). Targeting B cell receptor signalling in cancer: preclinical and clinical advances. Nature reviews. Cancer, 18(3), 148–167. https://doi.org/10.1038/nrc.2017.121
Fan, F., Yoo, H. J., Stock, S., Wang, L., Liu, Y., Schubert, M. L., Wang, S., Neuber, B., Hückelhoven-Krauss, A., Gern, U., Schmitt, A., Müller-Tidow, C., Dreger, P., Schmitt, M., & Sellner, L. (2021). Ibrutinib for improved chimeric antigen receptor T-cell production for chronic lymphocytic leukemia patients. International journal of cancer, 148(2), 419–428. https://doi.org/10.1002/ijc.33212
Herman, S., Montraveta, A., Niemann, C. U., Mora-Jensen, H., Gulrajani, M., Krantz, F., Mantel, R., Smith, L. L., McClanahan, F., Harrington, B. K., Colomer, D., Covey, T., Byrd, J. C., Izumi, R., Kaptein, A., Ulrich, R., Johnson, A. J., Lannutti, B. J., Wiestner, A., & Woyach, J. A. (2017). The Bruton Tyrosine Kinase (BTK) Inhibitor Acalabrutinib Demonstrates Potent On-Target Effects and Efficacy in Two Mouse Models of Chronic Lymphocytic Leukemia. Clinical cancer research : an official journal of the American Association for Cancer Research, 23(11), 2831–2841. https://doi.org/10.1158/1078-0432.CCR-16-0463
Byrd, J. C., Harrington, B., O'Brien, S., Jones, J. A., Schuh, A., Devereux, S., Chaves, J., Wierda, W. G., Awan, F. T., Brown, J. R., Hillmen, P., Stephens, D. M., Ghia, P., Barrientos, J. C., Pagel, J. M., Woyach, J., Johnson, D., Huang, J., Wang, X., Kaptein, A.,
… Furman, R. R. (2016). Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. The New England journal of medicine, 374(4), 323–332. https://doi.org/10.1056/NEJMoa1509981
Wang, M., Rule, S., Zinzani, P. L., Goy, A., Casasnovas, O., Smith, S. D., Damaj, G., Doorduijn, J., Lamy, T., Morschhauser, F., Panizo, C., Shah, B., Davies, A., Eek, R., Dupuis, J., Jacobsen, E., Kater, A. P., Le Gouill, S., Oberic, L., Robak, T., … Jurczak, W. (2018). Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet (London, England), 391(10121), 659–667. https://doi.org/10.1016/S0140-6736(17)33108-2
Acalabrutinib Approved for MCL. (2018). Cancer discovery, 8(1), OF6. https://doi.org/10.1158/2159-8290.CD-NB2017-158
Thompson, P. A., & Burger, J. A. (2018). Bruton's tyrosine kinase inhibitors: first and second generation agents for patients with Chronic Lymphocytic Leukemia (CLL). Expert opinion on investigational drugs, 27(1), 31–42. https://doi.org/10.1080/13543784.2018.1404027
Walter, H. S., Rule, S. A., Dyer, M. J., Karlin, L., Jones, C., Cazin, B., Quittet, P., Shah, N., Hutchinson, C. V., Honda, H., Duffy, K., Birkett, J., Jamieson, V., Courtenay-Luck, N., Yoshizawa, T., Sharpe, J., Ohno, T., Abe, S., Nishimura, A., Cartron, G., … Salles, G. (2016). A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies. Blood, 127(4), 411–419. https://doi.org/10.1182/blood-2015-08-664086
Kokabee, L., Wang, X., Sevinsky, C. J., Wang, W. L., Cheu, L., Chittur, S. V., Karimipoor, M., Tenniswood, M., & Conklin, D. S. (2015). Bruton's tyrosine kinase is a potential therapeutic target in prostate cancer. Cancer biology & therapy, 16(11), 1604–1615. https://doi.org/10.1080/15384047.2015.1078023
Grassilli, E., Pisano, F., Cialdella, A., Bonomo, S., Missaglia, C., Cerrito, M. G., Masiero, L., Ianzano, L., Giordano, F., Cicirelli, V., Narloch, R., D'Amato, F., Noli, B., Ferri, G. L., Leone, B. E., Stanta, G., Bonin, S., Helin, K., Giovannoni, R., & Lavitrano, M. (2016). A novel oncogenic BTK isoform is overexpressed in colon cancers and required for RAS-mediated transformation. Oncogene, 35(33), 4368–4378. https://doi.org/10.1038/onc.2015.504
Zucha, M. A., Wu, A. T., Lee, W. H., Wang, L. S., Lin, W. W., Yuan, C. C., & Yeh, C. T. (2015). Bruton's tyrosine kinase (Btk) inhibitor ibrutinib suppresses stem-like traits in ovarian cancer. Oncotarget, 6(15), 13255–13268. https://doi.org/10.18632/oncotarget.3658
Stiff, A., Trikha, P., Wesolowski, R., Kendra, K., Hsu, V., Uppati, S., McMichael, E., Duggan, M., Campbell, A., Keller, K., Landi, I., Zhong, Y., Dubovsky, J., Howard, J. H., Yu, L., Harrington, B., Old, M., Reiff, S., Mace, T., Tridandapani, S., … Carson, W. E., 3rd (2016). Myeloid-Derived Suppressor Cells Express Bruton's Tyrosine Kinase and Can Be Depleted in Tumor-Bearing Hosts by Ibrutinib Treatment. Cancer research, 76(8), 2125–2136. https://doi.org/10.1158/0008-5472.CAN-15-1490
Gunderson, A. J., Kaneda, M. M., Tsujikawa, T., Nguyen, A. V., Affara, N. I., Ruffell, B., Gorjestani, S., Liudahl, S. M., Truitt, M., Olson, P., Kim, G., Hanahan, D., Tempero, M. A., Sheppard, B., Irving, B., Chang, B. Y., Varner, J. A., & Coussens, L. M. (2016). Bruton Tyrosine Kinase-Dependent Immune Cell Cross-talk Drives Pancreas Cancer. Cancer discovery, 6(3), 270–285. https://doi.org/10.1158/2159-8290.CD-15-0827
Fraietta, J. A., Beckwith, K. A., Patel, P. R., Ruella, M., Zheng, Z., Barrett, D. M., Lacey, S. F., Melenhorst, J. J., McGettigan, S. E., Cook, D. R., Zhang, C., Xu, J., Do, P., Hulitt, J., Kudchodkar, S. B., Cogdill, A. P., Gill, S., Porter, D. L., Woyach, J. A., Long, M., … Maus, M. V. (2016). Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia. Blood, 127(9), 1117–1127. https://doi.org/10.1182/blood-2015-11-679134
Ruella, M., Kenderian, S. S., Shestova, O., Fraietta, J. A., Qayyum, S., Zhang, Q., Maus, M. V., Liu, X., Nunez-Cruz, S., Klichinsky, M., Kawalekar, O. U., Milone, M., Lacey, S. F., Mato, A., Schuster, S. J., Kalos, M., June, C. H., Gill, S., & Wasik, M. A. (2016). The Addition of the BTK Inhibitor Ibrutinib to Anti-CD19 Chimeric Antigen Receptor T Cells (CART19) Improves Responses against Mantle Cell Lymphoma. Clinical cancer research : an official journal of the American Association for Cancer Research, 22(11), 2684–2696. https://doi.org/10.1158/1078-0432.CCR-15-1527
Dubovsky, J. A., Beckwith, K. A., Natarajan, G., Woyach, J. A., Jaglowski, S., Zhong, Y., Hessler, J. D., Liu, T. M., Chang, B. Y., Larkin, K. M., Stefanovski, M. R., Chappell, D. L., Frissora, F. W., Smith, L. L., Smucker, K. A., Flynn, J. M., Jones, J. A., Andritsos, L. A.,
Maddocks, K., Lehman, A. M., … Byrd, J. C. (2013). Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood, 122(15), 2539–2549. https://doi.org/10.1182/blood-2013-06-507947
Aalipour, A., & Advani, R. H. (2014). Bruton's tyrosine kinase inhibitors and their clinical potential in the treatment of B-cell malignancies: focus on ibrutinib. Therapeutic advances in hematology, 5(4), 121–133. https://doi.org/10.1177/2040620714539906
Long, M., Beckwith, K., Do, P., Mundy, B. L., Gordon, A., Lehman, A. M., Maddocks, K. J., Cheney, C., Jones, J. A., Flynn, J. M., Andritsos, L. A., Awan, F., Fraietta, J. A., June, C. H., Maus, M. V., Woyach, J. A., Caligiuri, M. A., Johnson, A. J., Muthusamy, N., & Byrd, J. C. (2017). Ibrutinib treatment improves T cell number and function in CLL patients. The Journal of clinical investigation, 127(8), 3052–3064. https://doi.org/10.1172/JCI89756
Byrd, J. C., Brown, J. R., O'Brien, S., Barrientos, J. C., Kay, N. E., Reddy, N. M., Coutre, S., Tam, C. S., Mulligan, S. P., Jaeger, U., Devereux, S., Barr, P. M., Furman, R. R., Kipps, T. J., Cymbalista, F., Pocock, C., Thornton, P., Caligaris-Cappio, F., Robak, T., Delgado, J., … RESONATE Investigators (2014). Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. The New England journal of medicine, 371(3), 213–223. https://doi.org/10.1056/NEJMoa1400376
Coutré, S. E., Furman, R. R., Flinn, I. W., Burger, J. A., Blum, K., Sharman, J., Jones, J., Wierda, W., Zhao, W., Heerema, N. A., Johnson, A. J., Tran, A., Zhou, C., Bilotti, E., James, D. F., Byrd, J. C., & O'Brien, S. (2017). Extended Treatment with Single-Agent Ibrutinib at the 420 mg Dose Leads to Durable Responses in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Clinical cancer research : an official journal of the American Association for Cancer Research, 23(5), 1149–1155. https://doi.org/10.1158/1078-0432.CCR-16-1431
Burger, J. A., Tedeschi, A., Barr, P. M., Robak, T., Owen, C., Ghia, P., Bairey, O., Hillmen, P., Bartlett, N. L., Li, J., Simpson, D., Grosicki, S., Devereux, S., McCarthy, H., Coutre, S., Quach, H., Gaidano, G., Maslyak, Z., Stevens, D. A., Janssens, A., … RESONATE-2 Investigators (2015). Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. The New England journal of medicine, 373(25), 2425–2437. https://doi.org/10.1056/NEJMoa1509388
Dimopoulos, M. A., Tedeschi, A., Trotman, J., García-Sanz, R., Macdonald, D., Leblond, V., Mahe, B., Herbaux, C., Tam, C., Orsucci, L., Palomba, M. L., Matous, J. V., Shustik, C., Kastritis, E., Treon, S. P., Li, J., Salman, Z., Graef, T., Buske, C., & iNNOVATE Study Group and the European Consortium for Waldenström’s Macroglobulinemia (2018). Phase 3 Trial of Ibrutinib plus Rituximab in Waldenström's Macroglobulinemia. The New England journal of medicine, 378(25), 2399–2410. https://doi.org/10.1056/NEJMoa1802917
Burger J. A. (2019). Bruton Tyrosine Kinase Inhibitors: Present and Future. Cancer journal (Sudbury, Mass.), 25(6), 386–393. https://doi.org/10.1097/PPO.0000000000000412
Tam, C. S., Trotman, J., Opat, S., Burger, J. A., Cull, G., Gottlieb, D., Harrup, R., Johnston, P. B., Marlton, P., Munoz, J., Seymour, J. F., Simpson, D., Tedeschi, A., Elstrom, R., Yu, Y., Tang, Z., Han, L., Huang, J., Novotny, W., Wang, L., … Roberts, A. W. (2019). Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. Blood, 134(11), 851–859. https://doi.org/10.1182/blood.2019001160