ABT-869, a multitargeted receptor tyrosine kinase inhibitor: inhibition of FLT3 phosphorylation and signaling in acute myeloid leukemia
- Creators
- Shankar, Deepa B.
- Li, Junling
- Tapang, Paul
- McCall, J. Owen
- Pease, Lori J.
- Dai, Yujia
- Wei, Ru-Qi
- Albert, Daniel H.
- Bouska, Jennifer J.
- Osterling, Donald J.
- Guo, Jun
- Marcotte, Patrick A.
- Johnson, Eric F.
- Soni, Niru
- Hartandi, Kresna
- Michaelides, Michael R.
- Davidsen, Steven K.
- Priceman, Saul J.
- Chang, Jenny C.
- Rhodes, Katrin
- Shah, Neil
- Moore, Theodore B.
- Sakamoto, Kathleen M.
- Glaser, Keith B.
Abstract
In 15% to 30% of patients with acute myeloid leukemia (AML), aberrant proliferation is a consequence of a juxtamembrane mutation in the FLT3 gene (FMS-like tyrosine kinase 3–internal tandem duplication [FLT3-ITD]), causing constitutive kinase activity. ABT-869 (a multitargeted receptor tyrosine kinase inhibitor) inhibited the phosphorylation of FLT3, STAT5, and ERK, as well as Pim-1 expression in MV-4-11 and MOLM-13 cells (IC_(50) approximately 1-10 nM) harboring the FLT3-ITD. ABT-869 inhibited the proliferation of these cells (IC_(50) = 4 and 6 nM, respectively) through the induction of apoptosis (increased sub-G_(0)/G_1 phase, caspase activation, and PARP cleavage), whereas cells harboring wild-type (wt)–FLT3 were less sensitive. In normal human blood spiked with AML cells, ABT-869 inhibited phosphorylation of FLT3 (IC_(50) approximately 100 nM), STAT5, and ERK, and decreased Pim-1 expression. In methylcellulose-based colony-forming assays, ABT-869 had no significant effect up to 1000 nM on normal hematopoietic progenitor cells, whereas in AML patient samples harboring both FLT3-ITD and wt-FLT3, ABT-869 inhibited colony formation (IC_(50) = 100 and 1000 nM, respectively). ABT-869 dose-dependently inhibited MV-4-11 and MOLM-13 flank tumor growth, prevented tumor formation, regressed established MV-4-11 xenografts, and increased survival by 20 weeks in an MV-4-11 engraftment model. In tumors, ABT-869 inhibited FLT3 phosphorylation, induced apoptosis (transferase-mediated dUTP nick-end labeling [TUNEL]) and decreased proliferation (Ki67). ABT-869 is under clinical development for AML.
Additional Information
© 2007 American Society of Hematology. Submitted June 15, 2006; accepted December 9, 2006. D.B.S. is supported by the Hamburger endowment from the UCLA Jonsson Comprehensive Cancer Center. K.M.S. is a Scholar of the Lymphoma and Leukemia Society and is supported by the NIH (CA108545, HL75826, RHL083077A), the Department of Defense and the Diamond-Blackfan Anemia Foundation. Both T.B.M. and K.M.S. are funded by the UCLA Jonsson Comprehensive Cancer Center.Attached Files
Supplemental Material - 1.pdf
Supplemental Material - 2.pdf
Supplemental Material - 3.pdf
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Additional details
- PMCID
- PMC1852258
- Eprint ID
- 17537
- DOI
- 10.1182/blood-2006-06-029579
- Resolver ID
- CaltechAUTHORS:20100219-111915402
- Hamburger endowment, UCLA Jonsson Comprehensive Cancer Center
- CA108545
- NIH
- HL75826
- NIH
- RHL083077A
- NIH
- Department of Defense
- Diamond-Blackfan Anemia Foundation
- Created
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2010-02-22Created from EPrint's datestamp field
- Updated
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2021-11-08Created from EPrint's last_modified field