Successful Long-Term Ibrutinib Treatment in a Hemodialysis Patient With Leukemic Nonnodal Mantle Cell Lymphoma
6
Citation
7
Reference
10
Related Paper
Citation Trend
Keywords:
Hematology
breakpoint cluster region
Cite
Citations (3)
Bruton tyrosine kinase (BTK) is a critical effector molecule for B cell development and plays a major role in lymphoma genesis. Ibrutinib is the first-generation BTK inhibitor. Ibrutinib has off-target effects on EGFR, ITK, and Tec family kinases, which explains the untoward effects of ibrutinib. Resistance to ibrutinib was also reported. The C481S mutation in the BTK kinase domain was reported to be a major mechanism of resistance to ibrutinib. This review summarizes the clinical development of novel BTK inhibitors, ACP-196 (acalabrutinib), ONO/GS-4059, and BGB-3111.
Hematology
Cite
Citations (188)
Inhibition of Bruton's Tyrosine Kinase (BTK) by ibrutinib, an irreversible inhibitor, has dramatically improved the outcomes in both previously treated and naïve chronic lymphocytic leukemia (CLL) patients. Ibrutinib inactivates BTK through covalently binding to the cysteine 481 residue (C481) which then leads to the inhibition of autophosphorylation of BTK and the inactivation of downstream survival nexus. Although ibrutinib demonstrated >90% overall and event-free survival, about 25% of patients discontinue ibrutinib due to leukemia progression and intolerance. Patients that initially respond to treatment may develop resistance and the most prevalent resistance mechanism of ibrutinib is described as the point mutation affecting the C481 residue of BTK that results in disruption of ibrutinib binding and acquired ibrutinib resistance. Most common mutations are C481S and C481R. Vecabrutinib is a potent reversible BTK inhibitor that binds to BTK through noncovalent interactions. As vecabrutinib does not require binding to C481 residue, it retains its efficacy with mutant BTK in vitro. To better understand differential biology of Wild-Type (WT) and serine and arginine substituted BTK, we labelled MEC-1 cell line with green fluorescence protein (GFP) and overexpressed either BTKWT, BTKC481Sor BTKC481R that contributes to ibrutinib resistance. We selected MEC-1 cell line as it represents CLL disease and the phenotype of the cells share several characteristics of ex vivo CLL cells. We performed Reverse Phase Protein Array (RPPA) and mRNA-sequencing to determine and compare the proteomic and transcriptomic profiles of the MEC-1 cells harboring WT and mutant BTK. Ingenuity Pathway Analysis (IPA) of RPPA data revealed that overexpression of BTK WT leads to the enrichment of protein alterations involved in cell cycle regulation, B cell receptor signaling, PI3K/AKT signaling, PTEN signaling and ERK/MAPK signaling. IPA of RNAseq data upon BTK WT overexpression unraveled the top canonical pathways that include signaling through axonal guidance, ephrin receptor, c-AMP mediated, CXCR4 signaling and PTEN signaling. Comparative analysis of MEC-1 cells with mutant BTK (C481S vs C481R) using IPA distinguished the activated pathways in BTKC481Sharboring cells from cells that express BTKC481R. These results are being validated by western blot and qRT-PCR assays. Immunoblotting results showed that following 24, 48, and 72 hour of vecabrutinib (at 1 µM) treatment reduced p-BTK (Tyr223), p-PLCG2 (Tyr759) and p-ERK (Thr 202/Tyr 204) levels in MEC-1 cells with mutant BTK. These data indicate that vecabrutinib effectively inhibits BTK and its downstream signaling in the presence of mutant BTK, suggesting that vecabrutinib treatment may be a rational approach to overcome ibrutinib resistance.Citation Format: Burcu Aslan, Mikhila Mahendra, Michael D Peoples, Joe R. Marszalek, Christopher P Vellano, Xiaofeng Zheng, Jing Wang, Pietro Taverna, Varsha Gandhi. Vecabrutinib inhibits C481 mutated Bruton's tyrosine kinase and its downstream signaling in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 317.
Cite
Citations (1)
Abstract Ibrutinib (Imbruvica ™ ) is an irreversible, potent inhibitor of Bruton's tyrosine kinase ( BTK ). Over the last few years, ibrutinib has developed from a promising drug candidate to being approved by FDA for the treatment of three B cell malignancies, a truly remarkable feat. Few, if any medicines are monospecific and ibrutinib is no exception; already during ibrutinib's initial characterization, it was found that it could bind also to other kinases. In this review, we discuss the implications of such interactions, which go beyond the selective effect on BTK in B cell malignancies. In certain cases, the outcome of ibrutinib treatment likely results from the combined inhibition of BTK and other kinases, causing additive or synergistic, effects. Conversely, there are also examples when the clinical outcome seems unrelated to inhibition of BTK . Thus, more specifically, adverse effects such as enhanced bleeding or arrhythmias could potentially be explained by different interactions. We also predict that during long‐term treatment bone homoeostasis might be affected due to the inhibition of osteoclasts. Moreover, the binding of ibrutinib to molecular targets other than BTK or effects on cells other than B cell‐derived malignancies could be beneficial and result in new indications for clinical applications.
Cite
Citations (118)
Research over the role of Bruton's agammaglobulinemia tyrosine kinase (BTK) in B-lymphocyte development, differentiation, signaling and survival has led to better understanding of the pathogenesis of B-cell malignancies. Down-regulation of BTK activity is an attractive novel strategy for treating patients with B-cell malignancies. Ibrutinib (PCI-32765), a potent inhibitor of BTK induces impressive responses in B-cell malignancies through irreversible bond with cysteine-481 in the active site of BTK (TH/SH1 domain) and inhibits BTK phosphorylation on Tyr223. This review discussed in details the role of BTK in B-cell signaling, molecular interactions between B cell lymphoma/leukemia cells and their microenvironment. Clinical trials of the novel BTK inhibitor, ibrutinib (PCI-32765), in B cell malignancies were summarized.
Cite
Citations (75)
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.
Cite
Citations (2)
BACKGROUND. Ibrutinib is an effective targeted therapy for patients with chronic lymphocytic leukemia (CLL) that inhibits Bruton's tyrosine kinase (BTK), a kinase involved in B cell receptor signaling. METHODS. We used stable isotopic labeling with deuterated water (2H2O) to measure directly the effects of ibrutinib on leukemia cell proliferation and death in 30 patients with CLL. RESULTS. The measured average CLL cell proliferation ("birth") rate before ibrutinib therapy was 0.39% of the clone per day (range 0.17%-1.04%); this decreased to 0.05% per day (range 0%-0.36%) with treatment. Death rates of blood CLL cells increased from 0.18% per day (average, range 0%-0.7%) prior to treatment to 1.5% per day (range 0%-3.0%) during ibrutinib therapy, and they were even higher in tissue compartments. CONCLUSIONS. This study provides the first direct in vivo measurements to our knowledge of ibrutinib's antileukemia actions, demonstrating profound and immediate inhibition of CLL cell proliferation and promotion of high rates of CLL cell death. TRIAL REGISTRATION. This trial was registered at clinicaltrials.gov (NCT01752426). FUNDING. This study was supported by a Cancer Center Support Grant (National Cancer Institute grant P30 CA016672), an NIH grant (CA081554) from the National Cancer Institute, MD Anderson's Moon Shots Program in CLL, and Pharmacyclics, an AbbVie company.
Hematology
Cite
Citations (84)
breakpoint cluster region
Cite
Citations (3)
Macroglobulinemia
Lymphoplasmacytic Lymphoma
Cite
Citations (0)
Abstract PROteolysis TArgeting Chimeras (PROTACs) have emerged as a new and promising modality utilizing an event-driven MOA, whereby protein levels could be modulated by PROTAC-induced degradation by hijacking the ubiquitin-proteasome system. Starting from 2001, many target proteins have been studied, such as BET and kinase families as well as nuclear receptors. Bruton's tyrosine kinase (BTK) is an essential component of BCR pathway, which plays an important role in development, activation, proliferation, and survival of B lymphocytes. Ibrutinib is an irreversible inhibitor of BTK, and shows promising activity against multiple B lymphocyte derived malignancies. However, there remains a big concern about the development of Ibrutinib induced resistance by BTK C481S mutant. In our study, HSK26784 was found as a novel orally available BTK-PROTAC molecule, which could selectively degrade the BTK proteins. HSK26784 selectively degraded BTK proteins in Mino cell lines, with a half degradation concentration (DC50) of 22.9 nM. HSK26784 also effectively induced BTK degradation in mouse spleen, with a DC50 of 3.8 mg/kg. In addition, HSK26784 significantly inhibit the expression of CD69 on human PBMC cells after ex vivo BCR stimulation. HSK26784 could inhibit cell proliferation in many malignant B cell lines. In Ibrutinib sensitive cell lines, the inhibitory activity of HSK26784 is similar to that of Ibrutinib. While in the Ibrutinib non-sensitive cell lines, HSK26784 was more potent than Ibrutinib. Importantly, in the xenograft models, HSK26784 could also inhibit the tumor growth in a dose dependent manner. And HSK26784 achieved much better therapeutic effects than Ibrutinib. HSK26784 could inhibit the kinase activity of BTK wt and BTK C481S mutant, with IC50 of 11 nM and 14 nM respectively. It indicated that the efficacy of HSK26784 in BTK wt and BTK C481S mutant was comparable. HSK26784 showed good orally bioavailability in different species. The oral bio availabilities in mice, rats and dogs were 15.4 %, 11.8 % and 12.8 % respectively. In conclusion, HSK26784 is a promising BTK PROTAC degrader with better efficacy than Ibrutinib in multiple B lymphocytes. Citation Format: Meilin Qian, Fei Ye, Chen Zhang, Jianming Wang, Yuanli Zhang, Yangyang Cui, Linli Li, Xiaoli Gou, Jia Ni. HSK26784: An oral PROTAC-BTK degrader for multiple B lymphocyte derived malignancies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3761.
breakpoint cluster region
Cite
Citations (0)