Dasatinib inhibits the growth of molecularly heterogeneous myeloid leukemias.
OBJECTIVE
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).


METHODS
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 approximately 1 x 10(-9) mol/L. It also inhibited mutant Flt3 or Kit tyrosine phosphorylation at approximately 1 x 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 x 10(-9) mol/L. Primary AML blast cells exhibited a growth inhibition of <1 x 10(-6) mol/L. Cell lines that showed growth inhibition at approximately 1 x 10(-6) mol/L showed a G(1) 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.
Division of Pediatrics, Departments of Leukemia and Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas 60611, USA.
Bella S
BS
Guerrouahen
Muneyoshi
M
Futami
Christos
C
Vaklavas
Jukka
J
Kanerva
Zakary L
ZL
Whichard
Kenechi
K
Nwawka
Elisabeth G
EG
Blanchard
Francis Y
FY
Lee
Lisa J
LJ
Robinson
Robert
R
Arceci
Steven M
SM
Kornblau
Eric
E
Wieder
Yvon E
YE
Cayre
Seth J
SJ
Corey
D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics; D000069439:Dasatinib; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000473:pathology*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D011743:Pyrimidines; D013844:Thiazoles; D050760:Cyclin-Dependent Kinase Inhibitor p27; D019009:Proto-Oncogene Proteins c-kit; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D000069439:Dasatinib