The DOI matches its Crossref record; 48 of the 49 references it cites were found in a registry or an index.
Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes
Open accessAbstract
Given its critical role in T-cell signaling, interleukin-2-inducible kinase (ITK) is an appealing therapeutic target that can contribute to the pathogenesis of certain infectious, autoimmune, and neoplastic diseases. Ablation of ITK subverts Th2 immunity, thereby potentiating Th1-based immune responses. While small-molecule ITK inhibitors have been identified, none have demonstrated clinical utility. Ibrutinib is a confirmed irreversible inhibitor of Bruton tyrosine kinase (BTK) with outstanding clinical activity and tolerability in B-cell malignancies. Significant homology between BTK and ITK alongside in silico docking studies support ibrutinib as an immunomodulatory inhibitor of both ITK and BTK. Our comprehensive molecular and phenotypic analysis confirms ITK as an irreversible T-cell target of ibrutinib. Using ibrutinib clinical trial samples along with well-characterized neoplastic (chronic lymphocytic leukemia), parasitic infection (Leishmania major), and infectious disease (Listeria monocytogenes) models, we establish ibrutinib as a clinically relevant and physiologically potent ITK inhibitor with broad therapeutic utility. This trial was registered at www.clinicaltrials.gov as #NCT01105247 and #NCT01217749.
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“Although ibrutinib inhibits other similar kinases that contain C481, including ITK and BLK,7,22”
From Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib (2014) · cites this paper as [22]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“At relapse, none of the patients had mutations in other kinases containing a cysteine residue homologous to C481 in BTK that are irreversibly inhibited by ibrutinib”
From Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib (2014) · cites this paper as [22]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“mutations have not been observed in these other targets, findings that suggest that BTK is its critical target.”
From Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib (2014) · cites this paper as [22]
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Honigberg, L. A., Smith, A. M., Sirisawad, M., Verner, E., Loury, D., Chang, B., Li, S., Pan, Z., Thamm, D. H., Miller, R. A., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1004594107 · Cited by 1,561
Self-citationAdvani, 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., et al. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.42.7906 · Cited by 1,128 · cited 1×
“Irreversible ITK binding, ITK signal inhibition, and Th1-skewed cytokine patterns were also identified in CLL patients treated with ibrutinib in 2 clinical trials.(37,38) These findings were validated using a well-established mouse model of cutaneous leishmaniasis, and further clinical relevance was demonstrated using…”
BackgroundSelf-citationHerman, S. E. M., Gordon, A. L., Hertlein, E., Ramanunni, A., Zhang, X., Jaglowski, S., Flynn, J., Jones, J., Blum, K. A., Buggy, J. J., et al. (2011) · Blood · doi:10.1182/blood-2011-01-328484 · Cited by 807
Self-citationLong-term Outcome of 525 Patients With Mycosis Fungoides and Sézary Syndrome
Kim, Y. H., Liu, H. L., Mraz‐Gernhard, S., Varghese, A., & Hoppe, R. T. (2003) · Archives of Dermatology · doi:10.1001/archderm.139.7.857 · Cited by 652
Ramsay, A. G., Johnson, A. J., Lee, A. M., Görgün, G., Dieu, R. L., Blum, W. G., Byrd, J. C., & Gribben, J. G. (2008) · Journal of Clinical Investigation · doi:10.1172/jci35017 · Cited by 619
Self-citationMarks, D. I., Paietta, E. M., Moorman, A. V., Richards, S. M., Buck, G. A. N., Dewald, G. W., Ferrando, A. A., Fielding, A. K., Goldstone, A. H., Ketterling, R. P., et al. (2009) · Blood · doi:10.1182/blood-2009-08-231217 · Cited by 420
The B-cell receptor signaling pathway as a therapeutic target in CLL
Woyach, J. A., Johnson, A. J., & Byrd, J. C. (2012) · Blood · doi:10.1182/blood-2012-02-362624 · Cited by 412
Self-citationRequirement for Tec Kinases Rlk and Itk in T Cell Receptor Signaling and Immunity
Schaeffer, E. M., Debnath, J., Yap, G. S., McVicar, D. W., Liao, X. C., Littman, D. R., Sher, A., VARMUS, H. E., Lenardo, M. J., & Schwartzberg, P. L. (1999) · Science · doi:10.1126/science.284.5414.638 · Cited by 398
TEC FAMILY KINASES IN T LYMPHOCYTE DEVELOPMENT AND FUNCTION
Berg, L. J., Finkelstein, L. D., Lucas, J. A., & Schwartzberg, P. L. (2004) · Annual Review of Immunology · doi:10.1146/annurev.immunol.22.012703.104743 · Cited by 341
Liu, K., Bunnell, S. C., Gurniak, C. B., & Berg, L. J. (1998) · The Journal of Experimental Medicine · doi:10.1084/jem.187.10.1721 · Cited by 337
Impaired NFATc Translocation and Failure of Th2 Development in Itk-Deficient CD4+ T Cells
Fowell, D. J., Shinkai, K., Liao, X. C., Beebe, A. M., Coffman, R. L., Littman, D. R., & Locksley, R. M. (1999) · Immunity · doi:10.1016/s1074-7613(00)80115-6 · Cited by 306
Chronic lymphocytic leukemia cells induce changes in gene expression of CD4 and CD8 T cells
Görgün, G., Holderried, T. A. W., Zahrieh, D., Neuberg, D. S., & Gribben, J. G. (2005) · Journal of Clinical Investigation · doi:10.1172/jci24176 · Cited by 298
Chang, B. Y., Huang, M. M., Francesco, M. R., Chen, J., Sokolove, J. B., Magadala, P., Robinson, W. H., & Buggy, J. J. (2011) · Arthritis Research & Therapy · doi:10.1186/ar3400 · Cited by 231
Self-citationAltered Development of CD8+ T Cell Lineages in Mice Deficient for the Tec Kinases Itk and Rlk
Broussard, C., Fleischecker, C., Horai, R., Chetana, M., Venegas, A. M., Sharp, L. L., Hedrick, S. Μ., Fowlkes, B. J., & Schwartzberg, P. L. (2006) · Immunity · doi:10.1016/j.immuni.2006.05.011 · Cited by 193
Morrison, V. A. (2010) · Best Practice & Research Clinical Haematology · doi:10.1016/j.beha.2009.12.004 · Cited by 174
Signaling through Itk Promotes T Helper 2 Differentiation via Negative Regulation of T-bet
Miller, A. T., Wilcox, H. M., Lai, Z., & Berg, L. J. (2004) · Immunity · doi:10.1016/j.immuni.2004.06.009 · Cited by 171
Abnormal T-cell Function in B-cell Chronic Lymphocytic Leukaemia
Scrivener, S. G., Goddard, R., Kaminski, E. R., & Prentice, A. (2003) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/1042819021000029993 · Cited by 163
Marcotte, D. J., Liu, Y., Arduini, R. M., Hession, C. A., Miatkowski, K., Wildes, C. P., Cullen, P. F., Hong, V. S., Hopkins, B. T., Mertsching, E., et al. (2010) · Protein Science · doi:10.1002/pro.321 · Cited by 158
Loose, D., & de Wiele, C. V. (2009) · Cancer Biotherapy and Radiopharmaceuticals · doi:10.1089/cbr.2008.0593 · Cited by 110
Kashiwakura, J., Suzuki, N., Nagafuchi, H., Takeno, M., Takeba, Y., Shimoyama, Y., & Sakane, T. (1999) · The Journal of Experimental Medicine · doi:10.1084/jem.190.8.1147 · Cited by 95
Regulation of dendritic cell maturation and function by Bruton's tyrosine kinase via IL-10 and Stat3
Kawakami, Y., Inagaki, N., Salek‐Ardakani, S., Kitaura, J., Tanaka, H., Nagao, K., Kawakami, Y., Xiao, W., Nagai, H., Croft, M., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0509784103 · Cited by 93
Gómez‐Rodríguez, J., Kraus, Z., & Schwartzberg, P. L. (2011) · FEBS Journal · doi:10.1111/j.1742-4658.2011.08072.x · Cited by 80
Selective targeting of ITK blocks multiple steps of HIV replication
Readinger, J. A., Schiralli, G. M., Jiang, J.-K., Thomas, C., August, A., Henderson, A., & Schwartzberg, P. (2008) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0709659105 · Cited by 75
Abbott boosts investment in NRF2 activators for reducing oxidative stress
Crunkhorn, S. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3655 · Cited by 71
The Xid defect determines an improved clinical course of murine leishmaniasis in susceptible mice
Hoerauf, A., Solbach, W., Lohoff, M. D., & Röllinghoff, M. (1994) · International Immunology · doi:10.1093/intimm/6.8.1117 · Cited by 69
Jaglowski, S. M., Jones, J. A., Flynn, J. M., Andritsos, L. A., Maddocks, K. J., Blum, K. A., Grever, M. R., Geyer, S. M., Woyach, J. A., Johnson, A. J., et al. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2012.30.15_suppl.6508 · Cited by 65
Self-citationAu‐Yeung, B. B., Katzman, S. D., & Fowell, D. J. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.7.3895 · Cited by 64
T and B cells in B-chronic lymphocytic leukaemia: Faust, Mephistopheles and the pact with the Devil
Mellstedt, H., & Choudhury, A. (2005) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-005-0675-4 · Cited by 61
Porakishvili, N., Roschupkina, T., Kalber, T. L., Jewell, A. P., Patterson, K. G., Yong, K., & Lydyard, P. M. (2001) · Clinical & Experimental Immunology · doi:10.1046/j.1365-2249.2001.01639.x · Cited by 58
Atherly, L. O., Brehm, M. A., Welsh, R. M., & Berg, L. J. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.3.1571 · Cited by 57
Byrd, J. C., Furman, R. R., Coutre, S. E., Flinn, I. W., Burger, J. A., Blum, K. A., Sharman, J. P., Grant, B., Jones, J. A., Wierda, W. G., et al. (2012) · Blood · doi:10.1182/blood.v120.21.189.189 · Cited by 57
Self-citationHussain, A., Yu, L., Faryal, R., Mohammad, D. K., Mohamed, A. J., & Smith, C. I. E. (2011) · FEBS Journal · doi:10.1111/j.1742-4658.2011.08134.x · Cited by 50
Fowler, N. H., Sharman, J. P., Smith, S. M., Boyd, T. E., Grant, B., Kolibaba, K. S., Furman, R. R., Buggy, J. J., Loury, D. J., Hamdy, A., et al. (2010) · Blood · doi:10.1182/blood.v116.21.964.964 · Cited by 48
Self-citationVandenberghe, P., Verwilghen, J., Vaeck, F. V., & Ceuppens, J. L. (1993) · PubMed Central · Cited by 41
Gagliardi, M. C., Finocchi, A., Orlandi, P., Cursi, L., Cancrini, C., Moschese, V., MIYAWAKI, T., & Rossi, P. (2003) · Clinical & Experimental Immunology · doi:10.1046/j.1365-2249.2003.t01-1-02178.x · Cited by 39
Selective Expression Rather than Specific Function of Txk and Itk Regulate Th1 and Th2 Responses
Sahu, N., Venegas, A. M., Jankovic, D. L., Mitzner, W., Gómez‐Rodríguez, J., Cannons, J. L., Sommers, C. L., Love, P. E., Sher, A., Schwartzberg, P. L., et al. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.9.6125 · Cited by 38
Novel targeted therapies for mantle cell lymphoma
Alinari, L., Christian, B. A., & Baiocchi, R. A. (2012) · Oncotarget · doi:10.18632/oncotarget.426 · Cited by 37
Forbes, E., van Panhuys, N., Min, B., & Gros, G. S. L. (2009) · Immunology and Cell Biology · doi:10.1038/icb.2009.101 · Cited by 37
Cellular and Molecular Mechanisms of Tumor-Induced T-Cell Tolerance
Horna, P., & Sotomayor, E. M. (2007) · Current Cancer Drug Targets · doi:10.2174/156800907780006940 · Cited by 34
Itk inhibitors: a patent review
Lo, H. Y. (2010) · Expert Opinion on Therapeutic Patents · doi:10.1517/13543771003674409 · Cited by 30
Guo, W., Liu, R., Ono, Y., Ma, A., Martinez, A. D., Sanchez, E., Wang, Y., Huang, W., Mazloom, A., Li, J., et al. (2012) · Molecular Pharmacology · doi:10.1124/mol.112.079889 · Cited by 29
BTK inhibitor shows positive results in B cell malignancies
Harrison, C. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3656 · Cited by 28
Role of Itk signalling in the interaction between influenza A virus and T-cells
Fan, K., Jia, Y., Wang, S., Li, H., Wu, D., Wang, G., & Chen, J. (2012) · Journal of General Virology · doi:10.1099/vir.0.041228-0 · Cited by 28
Chronic lymphocytic leukemia: current and emerging treatment approaches.
Kay, N. E., Rai, K. R., & O'Brien, S. M. (2006) · PubMed · Cited by 23
Pollyea, D. A., Smith, S. M., Fowler, N. H., Boyd, T. E., Smith, A. M., Sirisawad, M., Honigberg, L. A., Hamdy, A., & Advani, R. H. (2009) · Blood · doi:10.1182/blood.v114.22.3713.3713 · Cited by 13
Son, J.-S., Chae, C.-S., Hwang, J., Park, Z., & Im, S. (2011) · PLoS ONE · doi:10.1371/journal.pone.0022042 · Cited by 13
Circumventing Immune Tolerance Through Epigenetic Modification
Dubovsky, J. A., Villagra, A., Powers, J. J., Wang, H., Pinilla-Ibarz, J. A., & Sotomayor, E. (2009) · Current Pharmaceutical Design · doi:10.2174/138161210790170120 · Cited by 12
Self-citationManaging patients with low-risk MDS.
Sekeres, M. A., Cosgrove, D., & Falco, A. (2006) · PubMed · Cited by 6
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Woyach, J. A., Furman, R. R., Liu, T.-M., Ozer, H. G., Zapatka, M., Ruppert, A. S., Xue, L., Li, D. H.-H., Steggerda, S. M., Versele, M., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1400029 · Cited by 1,275
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Self-citation
Metadata
- Authors
- 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., Furman, R., Sharman, J., Mishra, A., Caligiuri, M. A., Satoskar, A. R., Buggy, J. J., Muthusamy, N., Johnson, A. J., & Byrd, J. C.
- Affiliations
- Department of Internal Medicine, Division of Hematology,
- The Ohio State University (US)
- Pharmacyclics (United States) (US)
- Weill Cornell Medicine (US)
- Willamette Valley Cancer Institute and Research Center (US)
- Department of Pathology, and
- ORCID
- Beckwith, Kyle A.
- Natarajan, Gayathri
- Woyach, Jennifer A.
- Jaglowski, Samantha
- Chang, Betty Y.
- Chappell, Danielle L.
- Smith, Lisa L.
- Flynn, Joseph M.
- Jones, Jeffrey A.
- Andritsos, Leslie A.
- Maddocks, Kami
- Furman, Richard
- Sharman, Jeff
- Mishra, Anjali
- Caligiuri, Michael A.
- Satoskar, Abhay R.
- Muthusamy, Natarajan
- Johnson, Amy J.
- Byrd, John C.
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2013-10-10
- Volume
- 122
- Issue
- 15
- Pages
- 2539-2549
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC3795457
- OpenAlex
- W2089103836
- Cited by
- 810
- References
- 49
- Citations by year
- 2026: 30 · 2025: 43 · 2024: 55 · 2023: 51 · 2022: 70 · 2021: 98 · 2020: 68 · 2019: 71 · 2018: 71 · 2017: 70 · 2016: 65 · 2015: 67 · 2014: 43 · 2013: 5
- FWCI
- 29.54
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (4p01ca081534-16)
- National Cancer Institute (P01CA095426, P50CA140158, T32CA009338, 5 T32 CA009338-33-03, P30CA016058, K12CA133250, P01-CA-081534)
- Topics
- Health Sciences › Medicine › Hematology › Chronic Lymphocytic Leukemia Research
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- ibrutinib, irreversible kinase inhibitors, Bruton's tyrosine kinase, T cell signaling, Th1 response, Th2 immune response, chronic lymphocytic leukemia, Leishmania major, Listeria monocytogenes, immunomodulation
- MeSH terms
- Adenine, Animals, Disease Models, Animal, Enzyme Inhibitors, Humans, Leukemia, Listeriosis, Lymphocyte Activation, Piperidines, Protein-Tyrosine Kinases, Pyrazoles, Pyrimidines, Leishmaniasis, Cutaneous, CD8-Positive T-Lymphocytes, Th1 Cells, Th2 Cells, Jurkat Cells, Mice, Primary Cell Culture
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