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Activities of SYK and PLCγ2 Predict Apoptotic Response of CLL Cells to SRC Tyrosine Kinase Inhibitor Dasatinib
Abstract
Purpose B-cell receptor signaling plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL). However, blocking B-cell receptor signaling with dasatinib, an inhibitor of SRC kinase, produced variable results in preclinical and clinical studies. We aim to define the molecular mechanisms underlying the differential dasatinib sensitivity and to uncover more effective therapeutic targets in CLL. Experimental design Fresh CLL B cells were treated with dasatinib, and cell viability was followed. The CLL cases were then divided into good and poor responders. The cellular response was correlated with the activities of B-cell receptor signaling molecules, as well as with molecular and cytogenetic prognostic factors. Results Among 50 CLL cases, dasatinib treatment reduced cell viability by 2% to 90%, with an average reduction of 47% on day 4 of culture. The drug induced CLL cell death through the intrinsic apoptotic pathway mediated by reactive oxygen species. Unexpectedly, phosphorylation of SRC family kinases was inhibited by dasatinib in good, as well as poor, responders. As opposed to SRC family kinases, activities of two downstream molecules, SYK and phospholipase Cgamma2, correlate well with the apoptotic response of CLL cells to dasatinib. Conclusions Thus, SYK inhibition predicts cellular response to dasatinib. SYK, together with phospholipase Cgamma2, may serve as potential biomarkers to predict dasatinib therapeutic response in patients. From the pathog…
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“SYK/PLCγ2 activity is also suggested as a potential biomarker for responsiveness in the treatment of CLL and DLBCL, as their signaling activity correlated with cell death induced by treatment with the Src tyrosine kinase inhibitor, Dasatinib (133, 134).”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [134]
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BackgroundThe role of PLCγ2 in immunological disorders, cancer, and neurodegeneration
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“SYK/PLCγ2 activity is also suggested as a potential biomarker for responsiveness in the treatment of CLL and DLBCL, as their signaling activity correlated with cell death induced by treatment with the Src tyrosine kinase inhibitor, Dasatinib (133, 134).”
Background
Metadata
- Authors
- Song, Z., Lu, P., Furman, R. R., Leonard, J. P., Martin, P., Tyrell, L., Lee, F. Y., Knowles, D. M., Coleman, M., & Wang, Y. L.
- Affiliations
- Bristol-Myers Squibb (United States) (US)
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2010-01-14
- Volume
- 16
- Issue
- 2
- Pages
- 587-599
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2042132765
- Cited by
- 59
- References
- 0
- Citations by year
- 2025: 1 · 2024: 1 · 2021: 7 · 2020: 1 · 2019: 1 · 2017: 1 · 2016: 2 · 2015: 5 · 2014: 13 · 2013: 6 · 2012: 9
- FWCI
- 3.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Bristol-Myers Squibb
- Weill Cornell Medical College
- Topics
- Health Sciences › Medicine › Hematology › Chronic Lymphocytic Leukemia Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Health Sciences › Medicine › Hematology › Acute Lymphoblastic Leukemia research
- Keywords
- chronic lymphocytic leukemia, dasatinib, Syk, PLCγ2, Src family kinases, B cell receptor signaling, apoptosis, reactive oxygen species, predictive biomarkers, therapeutic target
- MeSH terms
- Dasatinib, Syk Kinase, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Enzyme Activation, Female, Humans, Male, Middle Aged, Prognosis, Protein-Tyrosine Kinases, Pyrimidines, Thiazoles, Tumor Cells, Cultured, Leukemia, Lymphocytic, Chronic, B-Cell, Cell Death, Apoptosis, src-Family Kinases, Protein Kinase Inhibitors, Intracellular Signaling Peptides and Proteins, Phospholipase C gamma, Biomarkers, Pharmacological
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