Targeting Bruton's tyrosine kinase with ibrutinib in B-cell malignancies

2015 ◽  
Vol 97 (5) ◽  
pp. 455-468 ◽  
Author(s):  
Y Wang ◽  
LL Zhang ◽  
RE Champlin ◽  
ML Wang
Keyword(s):  
Tyrosine Kinase ◽  
B Cell ◽  
Bruton’S Tyrosine Kinase ◽  
B Cell Malignancies ◽  
Bruton's Tyrosine Kinase

Phase I, first-in-human trial of Bruton’s tyrosine kinase inhibitor M7583 in patients with B-cell malignancies

2021 ◽  
pp. 1-8
Author(s):  
Wojciech Jurczak ◽  
Simon Rule ◽  
William Townsend ◽  
David Tucker ◽  
Barbara Sarholz ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Phase I ◽  
B Cell ◽  
Tyrosine Kinase Inhibitor ◽  
Kinase Inhibitor ◽  
Bruton’S Tyrosine Kinase ◽  
B Cell Malignancies ◽  
Bruton's Tyrosine Kinase ◽  
Human Trial

Resistance to Bruton's Tyrosine Kinase Inhibitors: The Achilles Heel of Their Success Story in Lymphoid Malignancies

Blood ◽  
2021 ◽  
Author(s):  
Deborah M. Stephens ◽  
John C Byrd
Keyword(s):  
Tyrosine Kinase ◽  
B Cell ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Lymphocytic Leukemia ◽  
Treatment Modalities ◽  
Bruton’S Tyrosine Kinase ◽  
B Cell Malignancies ◽  
Bruton's Tyrosine Kinase ◽  
Resistant Disease

Bruton's tyrosine kinase inhibitors (BTKi) have significantly changed the treatment landscape for patients with B-cell malignancies including chronic lymphocytic leukemia (CLL), Waldenstrom's macroglobulinemia (WM), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). Unfortunately, patients with BTKi resistant disease have shortened survival. Clinical and molecular risk factors, such as number of prior therapies and presence of TP53 mutations, can be used to predict patients at the highest risk of developing BTKi resistance. Many mechanisms of BTKi resistance have been reported with mutations in BTK and phospholipase C g 2 supported with the most data. The introduction of venetoclax has lengthened the survival of patients with BTKi resistant disease. Ongoing clinical trials with promising treatment modalities such as next-generation BTKi and chimeric antigen receptor T-cell therapy have reported promising efficacy in patients with BTKi resistant disease. Continued research focusing on resistance mechanisms and methods of how to circumvent resistance is needed to further prolong the survival of patients with BTKi resistant B-cell malignancies.

Activity of Bruton's Tyrosine Kinase (BTK) Inhibitor Ibrutinib (PCI-32765) in B-Cell Acute Lymphoblastic Leukemia (B-ALL).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2569-2569 ◽  
Author(s):  
Ekaterina Kim ◽  
Stefan Koehrer ◽  
Nathalie Y Rosin ◽  
Deborah A. Thomas ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Cell Lines ◽  
Cell Counting ◽  
Cell Phenotype ◽  
Bruton’S Tyrosine Kinase ◽  
B Cell Malignancies ◽  
Bruton's Tyrosine Kinase ◽  
Btk Inhibitor

Abstract Abstract 2569 Bruton's tyrosine kinase (BTK) is a member of the TEC family of non-receptor tyrosine kinases and is predominantly expressed in hematopoietic cells, except in T cells. BTK plays a prominent role in B cell receptor (BCR) signaling and several other pathways, including CXCR4 signaling, which is essential for lymphocyte homing. BTK activation downstream of the BCR leads to proliferation, differentiation, and survival of B cells. Functional BTK is necessary for normal B cell development, defective BTK result in a primary immunodeficiency called X-linked agammaglobulinemia (XLA). Because of the restricted expression and the B cell phenotype in BTK-deficient mice and XLA patients, BTK has become a promising therapeutic target in mature B cell malignancies. Ibrutinib is a selective, orally bioavailable, covalent BTK inhibitor currently studied in clinical trials in patients with Chronic Lymphocytic Leukemia (CLL) and other mature B cell malignancies. The importance of BTK in B-ALL is controversial. Initial study in childhood B-ALL revealed normal BTK protein levels, and gene expression profiling data from the St. Jude's group revealed BTK expression in B-ALL, but not in T-ALL. Other studies revealed abnormally spliced BTK mRNA and truncated BTK protein lacking kinase activity in some B-ALL samples. To explore the pre-clinical activity of ibrutinib in B-ALL, we used a panel of 14 B-ALL cell lines, representing pro-B (CD10+/−, TdT+, cyt Igμ-), pre-B (CD10+, TdT+, cyt Igμ+) and mature (CD10+/−, TdT-, surf IgM+) phenotypes. The panel included 4 Ph+/BCR-ABL1+ cell lines (Z-119, NALM-20, NALM-21, TOM-1). Western blot analysis revealed BTK expression in 12 out of 14 lines, while phospho-BTK (Y223) was present only in half of the cases. Effects of ibrutinib on B-ALL proliferation were tested in XTT assays, using increasing concentrations of ibrutinib (0.5 – 5 μM). All B-ALL cells responded to ibrutinib except for BTK-negative TANOUE cells. All other B-ALL cells displayed decreased proliferation with variable half maximal inhibitory concentrations of ibrutinib (IC50). The most sensitive cell lines (RCH-ACV, SMS-SB) had IC50 of < 1 μM; all BCR-ABL1+ cells showed IC50 < 3.5 μM (see Figure). We also analyzed inhibitory effects of ibrutinib on B-ALL cell proliferation by serial automated cell counting, which confirmed the XTT assay data. B-ALL cells viability was determined after incubation with ibrutinib, which induced only minor decreases after 3 days of incubation. Preliminary data with primary B-ALL samples revealed BTK protein expression in 5 out of 5 samples. In co-culture with KUSA-H1 stromal cells, primary B-ALL cells showed moderate levels of apoptosis, ranging from 10 – 25% after 3 days of incubation with 1 μM ibrutinib, which is similar to levels of ibrutinib-induced apoptosis in CLL. Collectively, these data demonstrate that the BTK inhibitor ibrutinib can interfere with B-ALL cell proliferation and survival, providing a rationale for clinical testing of this novel, well-tolerated targeted agent in patients with relapsed B-ALL. Disclosures: O'Brien: Pharmacyclics: Research support Other. Buggy:Pharmacyclics: Employment, Equity Ownership. Burger:Pharmacyclics: Consultancy, Research Funding.

scholarly journals Inhibitors targeting Bruton’s tyrosine kinase in cancers: drug development advances

Leukemia ◽  
2020 ◽  
Author(s):  
Tingyu Wen ◽  
Jinsong Wang ◽  
Yuankai Shi ◽  
Haili Qian ◽  
Peng Liu
Keyword(s):  
Tyrosine Kinase ◽  
B Cell ◽  
Drug Approval ◽  
Bruton’S Tyrosine Kinase ◽  
B Cell Malignancies ◽  
Bruton's Tyrosine Kinase ◽  
Btk Inhibitor ◽  
Btk Inhibitors ◽  
Potential Efficiency

Abstract Bruton’s tyrosine kinase (BTK) inhibitor is a promising novel agent that has potential efficiency in B-cell malignancies. It took approximately 20 years from target discovery to new drug approval. The first-in-class drug ibrutinib creates possibilities for an era of chemotherapy-free management of B-cell malignancies, and it is so popular that gross sales have rapidly grown to more than 230 billion dollars in just 6 years, with annual sales exceeding 80 billion dollars; it also became one of the five top-selling medicines in the world. Numerous clinical trials of BTK inhibitors in cancers were initiated in the last decade, and ~73 trials were intensively announced or updated with extended follow-up data in the most recent 3 years. In this review, we summarized the significant milestones in the preclinical discovery and clinical development of BTK inhibitors to better understand the clinical and commercial potential as well as the directions being taken. Furthermore, it also contributes impactful lessons regarding the discovery and development of other novel therapies.

scholarly journals Bruton's Tyrosine Kinase: From X-Linked Agammaglobulinemia Toward Targeted Therapy for B-Cell Malignancies

2014 ◽  
Vol 32 (17) ◽  
pp. 1830-1839 ◽  
Author(s):  
Sabine Ponader ◽  
Jan A. Burger
Keyword(s):  
Tyrosine Kinase ◽  
B Cell ◽  
Critical Role ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Bruton’S Tyrosine Kinase ◽  
B Cell Malignancies ◽  
Bruton's Tyrosine Kinase ◽  
Btk Inhibitor

Discovery of Bruton's tyrosine kinase (BTK) mutations as the cause for X-linked agammaglobulinemia was a milestone in understanding the genetic basis of primary immunodeficiencies. Since then, studies have highlighted the critical role of this enzyme in B-cell development and function, and particularly in B-cell receptor signaling. Because its deletion affects mostly B cells, BTK has become an attractive therapeutic target in autoimmune disorders and B-cell malignancies. Ibrutinib (PCI-32765) is the most advanced BTK inhibitor in clinical testing, with ongoing phase III clinical trials in patients with chronic lymphocytic leukemia and mantle-cell lymphoma. In this article, we discuss key discoveries related to BTK and clinically relevant aspects of BTK inhibitors, and we provide an outlook into clinical development and open questions regarding BTK inhibitor therapy.

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