Dasatinib Targets B-Lineage Cells but Does Not Provide an Effective Therapy for Myeloproliferative Disease in c-Cbl RING Finger Mutant Mice (original) (raw)
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Dasatinib Inhibits the Growth of Molecularly Heterogeneous Myeloid Leukemias
Clinical Cancer Research, 2010
Purpose-Dasatinib is a dual Src/Abl inhibitor, recently approved for Bcr-Abl+ leukemias with resistance or intolerance to prior therapy. Because Src kinases contribute to multiple blood cell functions by triggering a variety of signaling pathways, we hypothesized that their molecular targeting might lead to growth inhibition in acute myeloid leukemia (AML).
The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinib
Proceedings of the National Academy of Sciences, 2007
Dasatinib is a small-molecule kinase inhibitor used for the treatment of imatinib-resistant chronic myelogenous leukemia (CML). We have analyzed the kinases targeted by dasatinib by using an unbiased chemical proteomics approach to detect binding proteins directly from lysates of CML cells. Besides Abl and Src kinases, we have identified the Tec kinases Btk and Tec, but not Itk, as major binders of dasatinib. The kinase activity of Btk and Tec, but not of Itk, was inhibited by nanomolar concentrations of dasatinib in vitro and in cultured cells. We identified the gatekeeper residue as the critical determinant of dasatinib susceptibility. Mutation of Thr-474 in Btk to Ile and Thr-442 in Tec to Ile conferred resistance to dasatinib, whereas mutation of the corresponding residue in Itk (Phe-435) to Thr sensitized the otherwise insensitive Itk to dasatinib. The configuration of this residue may be a predictor for dasatinib sensitivity across the kinome. Analysis of mast cells derived from Btk-deficient mice suggested that inhibition of Btk by dasatinib may be responsible for the observed reduction in histamine release upon dasatinib treatment. Furthermore, dasatinib inhibited histamine release in primary human basophils and secretion of proinflammatory cytokines in immune cells. The observed inhibition of Tec kinases by dasatinib predicts immunosuppressive (side) effects of this drug and may offer therapeutic opportunities for inflammatory and immunological disorders.
Data from Dasatinib Inhibits the Growth of Molecularly Heterogeneous Myeloid Leukemias
Purpose: Dasatinib is a dual Src/Abl inhibitor recently approved for Bcr-Abl+ leukemias with resistance or intolerance to prior therapy. Because Src kinases contribute to multiple blood cell functions by triggering a variety of signaling pathways, we hypothesized that their molecular targeting might lead to growth inhibition in acute myeloid leukemia (AML).Experimental Design: We studied growth factor–dependent and growth factor–independent leukemic cell lines, including three cell lines expressing mutants of receptor tyrosine kinases (Flt3 or c-Kit) as well as primary AML blasts for responsiveness to dasatinib.Results: Dasatinib resulted in the inhibition of Src family kinases in all cell lines and blast cells at ∼1 × 10−9 mol/L. It also inhibited mutant Flt3 or Kit tyrosine phosphorylation at ∼1 × 10−6 mol/L. Mo7e cells expressing the activating mutation (codon 816) of c-Kit were most sensitive to growth inhibition with a GI50 of 5 × 10−9 mol/L. Primary AML blast cells exhibited a...
Cancer Research, 2008
Bcr-Abl tyrosine kinase inhibitors (TKI) are effective in inducing remissions in CML patients, but do not eliminate primitive CML hematopoietic cells. There is a need to identify mechanisms that contribute to retention of CML progenitors. Src family tyrosine kinases have been identified as potential mediators of Bcr-Abl induced leukemogenesis. Dasatinib (BMS-354825) is a potent dual Abl/Src kinase inhibitor approved for clinical use in CML patients. We evaluated Src activity in primitive human CML progenitors from different stages of disease, and investigated effects of Dasatinib on Src activity and downstream signaling pathways. P-Src expression was increased in CD34 + cells and CD34 + CD38 − cells in all phases of CML. Dasatinib demonstrated potent Src inhibitory activity in CML progenitors, inhibiting both Bcr-Abl dependent and independent Src activity. In contrast Imatinib inhibited only Bcr-Abl dependent Src activity. Dasatinib inhibited P-MAPK, P-Akt and P-STAT5 levels in CML progenitors in the absence of growth factors, but not in the presence of growth factors. A marked increase in P-MAPK levels seen in the presence of growth factors with Imatinib was much less prominent with Dasatinib. Dasatinib significantly suppressed CML CFC and LTC-IC but did not significantly alter the level of apoptosis-regulating proteins in CML CD34+ cells. Our results indicate that Dasatinib, in addition to potent anti-Bcr-Abl kinase activity, effectively inhibits Src kinase activity and downstream signaling pathways in CML progenitors but does not induce a strong pro-apoptotic response. These observations argue against a prominent role for Src kinases in persistence of primitive CML cells in TKI treated patients.
…, 2008
genes H unmutated IgV leukemia cells in vitro with preference for a subgroup of patients with The kinase inhibitor dasatinib induces apoptosis in chronic lymphocytic http://bloodjournal.hematologylibrary.org/cgi/content/full/112/4/1443 Updated information and services can be found at: (4075 articles) Neoplasia collections: Blood Articles on similar topics may be found in the following http://bloodjournal.hematologylibrary.org/misc/rights.dtl#repub\_requests Information about reproducing this article in parts or in its entirety may be found online at: http://bloodjournal.hematologylibrary.org/misc/rights.dtl#reprints Information about ordering reprints may be found online at: http://bloodjournal.hematologylibrary.org/subscriptions/index.dtl Information about subscriptions and ASH membership may be found online at: . Hematology; all rights reserved Src family kinases (SFKs) were described to be overexpressed in chronic lymphocytic leukemia (CLL). We wished to examine the effects of the Src and Abl kinase inhibitor dasatinib on the intracellular signaling and survival of CLL cells. Dasatinib showed a dose-and time-dependent reduction of global tyrosine phosphorylation and of activating phosphotyrosine levels of SFKs. Treatment with 100 nM dasatinib led to decreased levels of the activated, phosphorylated forms of Akt, Erk1/2, and p38, and induced PARP cleavage through caspase activity. In Mec1 and JVM-3 cell lines, dasatinib increased p53 protein levels and inhibited proliferation. In freshly isolated CLL cells, dasatinib reduced the expression of Mcl-1 and Bcl-x L . Combination of 5 M dasatinib and fludarabine increased the apoptosis induction of each by approximately 50%.
In vivo, ex vivo and in vitro dasatinib activity in chronic lymphocytic leukemia
Oncology Letters, 2021
Dasatinib inhibits the breakpoint cluster region-Abelson murine leukemia 1 (BCR-ABL1) gene along with other kinases known to be overexpressed and abnormally active in patients with chronic lymphocytic leukemia (CLL). The current study used primary leukemic cells obtained from 53 patients with CLL that were treated with dasatinib. A 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) assay and Annexin V staining was performed to assess the cytotoxic effects of dasatinib treatment. The XTT assay revealed that the median cytotoxicity of dasatinib was 8.30% (range, 0.00–77.89%). Due to high dispersion of dasatinib activity, patients were divided into sensitive (n=27; 50.94%; median cytotoxicity, 22.81%) and resistant groups (n=26; 49.06%; median cytotoxicity, 0.00%). A median cytotoxicity of 8.30% was selected as a cut off value. Using Annexin V staining and flow cytometry on exemplary sensitive and resistant CLL samples, it was revealed that 17.71 and 1.84% o...
Targeting mutated protein tyrosine kinases and their signaling pathways in hematologic malignancies
Haematologica, 2005
Over the last decade, major advances have been made in the elucidation of mechanisms involved in leukemogenesis, and this is particularly true with regard to deregulated protein tyrosine kinase (PTK) activation. This progress had led to the development of small molecules that specifically inhibit the abnormally activated kinase. The first example of such targeted therapy is imatinib-mesylate, an inhibitor of the BCR-ABL fusion gene that is found in more than 90% of patients with Philadelphia positive (Ph+) chronic myeloid leukemia (CML) and in 20-30% of those with Ph+ acute lymphoblastic leukemia (ALL). The excellent clinical results obtained with imatinib in CML have completely changed the therapeutic approach to this disease, and imatinib is now the gold standard for treatment of newly diagnosed CML. This has instigated a tremendous effort to develop targeted PTK therapy based on the presence of over 40 chromosomal translocations that lead to deregulation of 12 different PTK assoc...