The kinase inhibitor dasatinib induces apoptosis in chronic lymphocytic leukemia cells in vitro with preference for a subgroup of patients with unmutated IgVH genes

Veldurthy, Aditya; Patz, Michaela; Hagist, Susanne; Pallasch, Christian P.; Wendtner, Clemens‐Martin; Hallek, Michael; Krause, Günter

doi:10.1182/blood-2007-11-123984

Cited by 90 publications

(115 citation statements)

References 49 publications

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“…Therefore, these kinases seem not to be directly involved in cell survival mechanisms. Our results for dasatinib are in agreement with published data 4 and suggest that this drug, despite targeting a multitude of kinase pathways including BCR signaling through BTK, 37 does not directly target any pathways that peripheral CLL cells may be 'addicted' to. In line with the notion that the viability of peripheral CLL cells may not critically depend on BCR signaling, we did not likewise observe any substantial effect of the SYK inhibitor R406.…”

Section: Discussionsupporting

confidence: 82%

“…Recently, dasatinib, a drug that was first approved for imatinib-refractory CML, showed promising in vitro activity in chronic lymphocytic leukemia (CLL) cells. 4 However, to date no kinase inhibitor has been approved for the treatment of CLL. This disease is generally characterized by the accumulation of CD5 þ /CD19 þ B-cells, which seem to escape apoptosis, in the peripheral blood and lymphoid organs.…”

Section: Introductionmentioning

confidence: 99%

“…5 Protein kinase inhibitors like dasatinib or flavopiridol are currently investigated in preclinical development and in clinical trials. 4,6 In the variable clinical course of the disease, the expression of the tyrosine kinase ZAP-70 represents a prognostic factor of poor clinical course. 7 However, the relevant signaling pathways and targets as well as the clinical impact of kinase inhibitors in CLL remain to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Chemoproteomics-based kinome profiling and target deconvolution of clinical multi-kinase inhibitors in primary chronic lymphocytic leukemia cells

Kruse¹,

Pallasch

Bantscheff³

et al. 2010

Leukemia

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The pharmacological induction of apoptosis in neoplastic B cells presents a promising therapeutic avenue for the treatment of chronic lymphocytic leukemia (CLL). We profiled a panel of clinical multi-kinase inhibitors for their ability to induce apoptosis in primary CLL cells. Whereas inhibitors targeting a large number of receptor and intracellular tyrosine kinases including c-KIT, FLT3, BTK and SYK were comparatively inactive, the CDK inhibitors BMS-387032 and flavopiridol showed marked efficacy similar to staurosporine. Using the kinobeads proteomics method, kinase expression profiles and binding profiles of the inhibitors to target protein complexes were quantitatively monitored in CLL cells. The targets most potently affected were CDK9, cyclin T1, AFF3/4 and MLLT1, which may represent four subunits of a deregulated positive transcriptional elongation factor (p-TEFb) complex. Albeit with lower potency, both drugs also bound the basal transcription factor BTF2/TFIIH containing CDK7. Staurosporine and geldanamycin do not affect these targets and thus seem to exhibit a different mechanism of action. The data support a critical role of p-TEFb inhibitors in CLL that supports their future clinical development.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Chemoproteomics-based kinome profiling and target deconvolution of clinical multi-kinase inhibitors in primary chronic lymphocytic leukemia cells

Kruse¹,

Pallasch

Bantscheff³

et al. 2010

Leukemia

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“…Activation of this signalosome then leads to induction of calcium signaling, as well as of Akt, NF-kB, and mitogen-activated protein kinase (MAPK) pathway activation (12). Lyn and Syk are thought to be key mediators of BCR signaling in CLL cells because both these kinases are overexpressed, and both have been shown to have cytoprotective roles (13,14) in studies using SFK inhibitors such as dasatinib (15) as well as Syk inhibitors such as fostamatinib disodium (14). However, the mechanism of BCR signaling in CLL cells is incompletely understood because additional factors not normally involved in BCR signaling are also present.…”

Section: Introductionmentioning

confidence: 99%

LCK Is an Important Mediator of B-Cell Receptor Signaling in Chronic Lymphocytic Leukemia Cells

Talab

Allen

Thompson

et al. 2013

Molecular Cancer Research

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B-cell receptor (BCR) signals promote survival of chronic lymphocytic leukemia (CLL) cells, and it is believed that overexpressed and constitutively active Lyn mediates this signaling. Here, we show that CLL cells express lymphocyte-specific protein tyrosine kinase (LCK) and that inhibition of this Src family tyrosine kinase with the specific inhibitor [4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[3,2-d]pyrimidin-7-yl-cyclopentane (Lck-i)], or reduction of its expression with siRNA, blocks the induction of CD79a, Syk, inhibitor of IkB kinase (IKK), Akt, and extracellular signal-regulated kinase (ERK) phosphorylation by BCR cross-linking in these cells. Furthermore, we show that CLL cells with high levels of LCK expression have higher levels of BCR-mediated IKK, Akt, and ERK phosphorylation as well as cell survival than CLL cells with low levels of LCK expression. We also show that treatment of CLL cells with Lck-i inhibits BCR cross-linking-induced cell survival. Taken together, these data show a major role for LCK in proximal and distal BCR-mediated signaling in CLL cells and suggest that LCK expression is important in the pathogenesis of this disease. On a clinical level, these studies advocate the use of specific LCK inhibitors in the treatment of progressive CLL. Mol Cancer Res; 11(5); 541-54. Ó2013 AACR.

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“…Further in vitro experiments showed also synergistic effects of dasatinib with chlorambucil and fludarabine [49]. CLL cells with unmutated IGHV seem to respond better than those with mutation [50].…”

Section: Dasatinibmentioning

confidence: 92%

Refractory chronic lymphocytic leukemia - new therapeutic strategies

Schnaiter

Stilgenbauer

2010

Oncotarget

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AbstrAct:Treatment outcome of chronic lymphocytic leukemia (CLL) has considerably improved since the introduction of fludarabine (F) as part of the standard therapy. Nevertheless, refractoriness to fludarabine occurs in a significant number of patients and is associated with an unfavorable prognosis. Important risk factors are 17p deletion and/or mutation of TP53. For this subgroup the CD52 antibody alemtuzumab (A) presents a new treatment approach and has already been approved. Meanwhile we have to face also refractoriness to alemtuzumab. Importantly, the monoclonal CD20 antibody ofatumumab has now shown efficacy in F and A double-refractory CLL. The next generation CD20 antibody GA-101 is currently compared to rituximab (R) and will possibly be its more potent successor. Further B-cell antigens are targeted by lumiliximab (CD23), TRU-016 (CD37) and blinatumomab (CD19). Apart from monoclonal antibody therapies, a great number of small molecules are examined for the treatment of refractory and relapsed CLL. Most of these agents aim to overcome apoptosis resistance in CLL cells or influence the microenvironment. Typical targets are regulators of the cell cycle and antiapoptotic molecules like the members of the Bcl-2 family. Up to now the most promising agents appear to be flavopiridol and lenalidomide among others.

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The kinase inhibitor dasatinib induces apoptosis in chronic lymphocytic leukemia cells in vitro with preference for a subgroup of patients with unmutated IgVH genes

Cited by 90 publications

References 49 publications

Chemoproteomics-based kinome profiling and target deconvolution of clinical multi-kinase inhibitors in primary chronic lymphocytic leukemia cells

Chemoproteomics-based kinome profiling and target deconvolution of clinical multi-kinase inhibitors in primary chronic lymphocytic leukemia cells

LCK Is an Important Mediator of B-Cell Receptor Signaling in Chronic Lymphocytic Leukemia Cells

Refractory chronic lymphocytic leukemia - new therapeutic strategies

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