The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinib

Hantschel, Oliver; Rix, Uwe; Schmidt, Uwe; Bürckstümmer, Tilmann; Kneidinger, Michael; Schütze, Gregor; Colinge, Jacques; Bennett, Keiryn L.; Ellmeier, Wilfried; Valent, Peter; Superti‐Furga, Giulio

doi:10.1073/pnas.0702654104

Cited by 259 publications

(234 citation statements)

References 35 publications

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“…Despite high protease activity particularly affecting BCR-ABL in the primary CML patient cell lysates, 19 we were still able to identify ABL and ARG peptides in both patient samples. As with dasatinib, 13,14,16 the TEC family kinases are also prominently targeted by bosutinib, with three of five members identified. In particular, BTK (IC 50 ¼ 2.5 nM) was a major binding protein in all cell types.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, we previously used a chemical proteomic approach in which we immobilized coupleable analogs of imatinib, dasatinib and nilotinib and exposed them to total cell lysates not only of the BCR-ABL-positive K562 cell line, but also to extracts of primary CML patient cells, thereby identifying and subsequently validating both novel kinase (BTK, DDR1) and nonkinase (NQO2) targets. 14,16 Here, we used a combined chemical proteomic and in vitro profiling method to evaluate (i) the natural target profile of bosutinib in primary CML and K562 cells and (ii) the activity of bosutinib versus dasatinib against over 270 recombinant kinases, thereby maximizing the cross-section of the kinome under investigation. This combined approach revealed that bosutinib, similar to dasatinib, is also a broad specificity kinase inhibitor, targeting not only SRC and ABL kinases, but also TEC family kinases, including BTK, which is known to have host immunomodulatory activity.…”

Section: Introductionmentioning

confidence: 99%

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Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells

et al. 2008

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The detailed molecular mechanism of action of secondgeneration BCR-ABL tyrosine kinase inhibitors, including perturbed targets and pathways, should contribute to rationalized therapy in chronic myeloid leukemia (CML) or in other affected diseases. Here, we characterized the target profile of the dual SRC/ABL inhibitor bosutinib employing a two-tiered approach using chemical proteomics to identify natural binders in whole cell lysates of primary CML and K562 cells in parallel to in vitro kinase assays against a large recombinant kinase panel. The combined strategy resulted in a global survey of bosutinib targets comprised of over 45 novel tyrosine and serine/ threonine kinases. We have found clear differences in the target patterns of bosutinib in primary CML cells versus the K562 cell line. A comparison of bosutinib with dasatinib across the whole kinase panel revealed overlapping, but distinct, inhibition profiles. Common among those were the SRC, ABL and TEC family kinases. Bosutinib did not inhibit KIT or platelet-derived growth factor receptor, but prominently targeted the apoptosis-linked STE20 kinases. Although in vivo bosutinib is inactive against ABL T315I, we found this clinically important mutant to be enzymatically inhibited in the midnanomolar range. Finally, bosutinib is the first kinase inhibitor shown to target CAMK2G, recently implicated in myeloid leukemia cell proliferation.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells

et al. 2008

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“…[3][4][5] The kinase inhibition profile of dasatinib is broad and includes SRC and TEC kinases not inhibited by imatinib. 6,7 This may be therapeutically advantageous, but as long-term effects on normal cells are largely unknown, significant side effects may emerge.…”

Section: Introductionmentioning

confidence: 99%

Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy

et al. 2009

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Dasatinib, a broad-spectrum tyrosine kinase inhibitor (TKI), predominantly targets BCR-ABL and SRC oncoproteins and also inhibits off-target kinases, which may result in unexpected drug responses. We identified 22 patients with marked lymphoproliferation in blood while on dasatinib therapy. Clonality and immunophenotype were analyzed and related clinical information was collected. An abrupt lymphocytosis (peak count range 4-20 Â 10 9 /l) with large granular lymphocyte (LGL) morphology was observed after a median of 3 months from the start of therapy and it persisted throughout the therapy. Fifteen patients had a cytotoxic T-cell and seven patients had an NK-cell phenotype. All T-cell expansions were clonal. Adverse effects, such as colitis and pleuritis, were common (18 of 22 patients) and were preceded by LGL lymphocytosis. Accumulation of identical cytotoxic T cells was also detected in pleural effusion and colon biopsy samples. Responses to dasatinib were good and included complete, unexpectedly long-lasting remissions in patients with advanced leukemia. In a phase II clinical study on 46 Philadelphia chromosome-positive acute lymphoblastic leukemia, patients with lymphocytosis had superior survival compared with patients without lymphocytosis. By inhibiting immunoregulatory kinases, dasatinib may induce a reversible state of aberrant immune reactivity associated with good clinical responses and a distinct adverse effect profile.

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“…[42][43][44] When we assayed the proliferation of NUP214-ABL1-expressing Ba/F3 cells in the presence of dasatinib, proliferation was inhibited at two-to threefold lower dasatinib concentrations than that of BCR-ABL1-transformed Ba/F3 cells (Figure 5c). This is a much smaller difference than the 55-fold difference in imatinib sensitivity that we observed between the two cell lines.…”

Section: Nup214-abl1 and Bcr-abl1 Phosphorylate A Different Spectrummentioning

confidence: 99%

Intrinsic differences between the catalytic properties of the oncogenic NUP214-ABL1 and BCR-ABL1 fusion protein kinases

Keersmaecker¹,

Versele²,

Cools³

et al. 2008

Leukemia

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The NUP214-ABL1 fusion kinase has recently been identified in 6% of patients with T-cell acute lymphoblastic leukemia. In contrast to the more common oncogenic ABL1 fusion BCR-ABL1, NUP214-ABL1 localizes to the nuclear pore complexes and has attenuated transforming properties in hematopoietic cells and in mouse bone marrow transplant models. We have performed a thorough biochemical comparative analysis of NUP214-ABL1 and BCR-ABL1 and show that, despite their common tyrosine kinase domain, the two fusion proteins differ in many critical catalytic properties. NUP214-ABL1 has lower in vitro tyrosine kinase activity, which is in agreement with the absence of phosphorylation on its activation loop. NUP214-ABL1 was more sensitive to imatinib (Glivec) than BCR-ABL1 in vitro and in cells, indicating a different activation state and conformation of the two ABL1 fusion kinases. Using a peptide array, we identified differences in the spectrum and efficiency of substrate peptide phosphorylation and a differential involvement of Src kinases in downstream signaling. These results clearly indicate that different fusion partners of the same kinase can determine not only localization, but also critical functional properties of the enzyme such as inhibitor sensitivity and substrate preference, with subsequent differences in downstream signaling effectors and likely consequences in disease pathogenesis.

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The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinib

Cited by 259 publications

References 35 publications

Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells

Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells

Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy

Intrinsic differences between the catalytic properties of the oncogenic NUP214-ABL1 and BCR-ABL1 fusion protein kinases

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