Dasatinib inhibits the growth of molecularly heterogeneous myeloid leukemias

Bella S. Guerrouahen, Muneyoshi Futami, Christos Vaklavas, Jukka Kanerva, Zakary L. Whichard, Kenechi Nwawka, Elisabeth G. Blanchard, Francis Y. Lee, Lisa J. Robinson, Robert Arceci, Steven M. Kornblau, Eric Wieder, Yvon E. Cayre, Seth J. Corey

Research output: Contribution to journalArticle

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Abstract

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 GI 50 of 5 × 10 -9 mol/L. Primary AML blast cells exhibited a growth inhibition of <1 × 10 -6 mol/L. Cell lines that showed growth inhibition at ∼1 × 10 -6 mol/L showed a G1 cell cycle arrest and correlated with accumulation of p21 and p27 protein. The addition of rapamycin or cytotoxic agents enhanced growth inhibition. Dasatinib also caused the apoptosis of Mo7e cells expressing oncogenic Kit. Conclusions: Although all of the precise targets for dasatinib are not known, this multikinase inhibitor causes either growth arrest or apoptosis in molecularly heterogeneous AML. The addition of cytotoxic or targeted agents can enhance its effects.

Original languageEnglish
Pages (from-to)1149-1158
Number of pages10
JournalClinical Cancer Research
Volume16
Issue number4
DOIs
Publication statusPublished - 15 Feb 2010
Externally publishedYes

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Myeloid Leukemia
Acute Myeloid Leukemia
Growth
Cell Line
src-Family Kinases
Intercellular Signaling Peptides and Proteins
Apoptosis
G1 Phase Cell Cycle Checkpoints
Cytotoxins
Receptor Protein-Tyrosine Kinases
Sirolimus
Codon
Tyrosine
Dasatinib
Blood Cells
Leukemia
Research Design
Phosphorylation
Mutation
Proteins

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Guerrouahen, B. S., Futami, M., Vaklavas, C., Kanerva, J., Whichard, Z. L., Nwawka, K., ... Corey, S. J. (2010). Dasatinib inhibits the growth of molecularly heterogeneous myeloid leukemias. Clinical Cancer Research, 16(4), 1149-1158. https://doi.org/10.1158/1078-0432.CCR-09-2416

Dasatinib inhibits the growth of molecularly heterogeneous myeloid leukemias. / Guerrouahen, Bella S.; Futami, Muneyoshi; Vaklavas, Christos; Kanerva, Jukka; Whichard, Zakary L.; Nwawka, Kenechi; Blanchard, Elisabeth G.; Lee, Francis Y.; Robinson, Lisa J.; Arceci, Robert; Kornblau, Steven M.; Wieder, Eric; Cayre, Yvon E.; Corey, Seth J.

In: Clinical Cancer Research, Vol. 16, No. 4, 15.02.2010, p. 1149-1158.

Research output: Contribution to journalArticle

Guerrouahen, BS, Futami, M, Vaklavas, C, Kanerva, J, Whichard, ZL, Nwawka, K, Blanchard, EG, Lee, FY, Robinson, LJ, Arceci, R, Kornblau, SM, Wieder, E, Cayre, YE & Corey, SJ 2010, 'Dasatinib inhibits the growth of molecularly heterogeneous myeloid leukemias', Clinical Cancer Research, vol. 16, no. 4, pp. 1149-1158. https://doi.org/10.1158/1078-0432.CCR-09-2416
Guerrouahen, Bella S. ; Futami, Muneyoshi ; Vaklavas, Christos ; Kanerva, Jukka ; Whichard, Zakary L. ; Nwawka, Kenechi ; Blanchard, Elisabeth G. ; Lee, Francis Y. ; Robinson, Lisa J. ; Arceci, Robert ; Kornblau, Steven M. ; Wieder, Eric ; Cayre, Yvon E. ; Corey, Seth J. / Dasatinib inhibits the growth of molecularly heterogeneous myeloid leukemias. In: Clinical Cancer Research. 2010 ; Vol. 16, No. 4. pp. 1149-1158.
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AU - Futami, Muneyoshi

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AU - Whichard, Zakary L.

AU - Nwawka, Kenechi

AU - Blanchard, Elisabeth G.

AU - Lee, Francis Y.

AU - Robinson, Lisa J.

AU - Arceci, Robert

AU - Kornblau, Steven M.

AU - Wieder, Eric

AU - Cayre, Yvon E.

AU - Corey, Seth J.

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N2 - 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 GI 50 of 5 × 10 -9 mol/L. Primary AML blast cells exhibited a growth inhibition of <1 × 10 -6 mol/L. Cell lines that showed growth inhibition at ∼1 × 10 -6 mol/L showed a G1 cell cycle arrest and correlated with accumulation of p21 and p27 protein. The addition of rapamycin or cytotoxic agents enhanced growth inhibition. Dasatinib also caused the apoptosis of Mo7e cells expressing oncogenic Kit. Conclusions: Although all of the precise targets for dasatinib are not known, this multikinase inhibitor causes either growth arrest or apoptosis in molecularly heterogeneous AML. The addition of cytotoxic or targeted agents can enhance its effects.

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