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ABT-869, a multitargeted receptor tyrosine kinase inhibitor: inhibition of FLT3 phosphorylation and signaling in acute myeloid leukemia

Shankar, Deepa B. and Li, Junling and Tapang, Paul and McCall, J. Owen and Pease, Lori J. and Dai, Yujia and Wei, Ru-Qi and Albert, Daniel H. and Bouska, Jennifer J. and Osterling, Donald J. and Guo, Jun and Marcotte, Patrick A. and Johnson, Eric F. and Soni, Niru and Hartandi, Kresna and Michaelides, Michael R. and Davidsen, Steven K. and Priceman, Saul J. and Chang, Jenny C. and Rhodes, Katrin and Shah, Neil and Moore, Theodore B. and Sakamoto, Kathleen M. and Glaser, Keith B. (2007) ABT-869, a multitargeted receptor tyrosine kinase inhibitor: inhibition of FLT3 phosphorylation and signaling in acute myeloid leukemia. Blood, 109 (8). pp. 3400-3408. ISSN 0006-4971. PMCID PMC1852258. https://resolver.caltech.edu/CaltechAUTHORS:20100219-111915402

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PDF (Table S1. Percentage of blasts in the bone marrow from patients with AML at diagnosis (PDF, 11 KB)) - Supplemental Material
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PDF (Figure S1. Hierarchial cluster heatmap of Ki values (nM) for various FLT3 and VEGFR/PDGFR inhibitors (PDF, 37.9 KB)) - Supplemental Material
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PDF (Figure S2. Dose response of ABT-869 in wt-FLT3 AML patient samples (PDF, 29.7 KB)) - Supplemental Material
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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1182/blood-2006-06-029579DOIArticle
http://bloodjournal.hematologylibrary.org/cgi/content/abstract/109/8/3400PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1852258/PubMed CentralArticle
ORCID:
AuthorORCID
Sakamoto, Kathleen M.0000-0003-0494-8838
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.
Funders:
Funding AgencyGrant Number
Hamburger endowment, UCLA Jonsson Comprehensive Cancer CenterUNSPECIFIED
NIHCA108545
NIHHL75826
NIHRHL083077A
Department of DefenseUNSPECIFIED
Diamond-Blackfan Anemia FoundationUNSPECIFIED
Issue or Number:8
PubMed Central ID:PMC1852258
Record Number:CaltechAUTHORS:20100219-111915402
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20100219-111915402
Official Citation:Deepa B Shankar, Junling Li, Paul Tapang, J. Owen McCall, Lori J Pease, Yujia Dai, Ru-Qi Wei, Daniel H Albert, Jennifer J Bouska, Donald J Osterling, Jun Guo, Patrick A Marcotte, Eric F Johnson, Niru Soni, Kresna Hartandi, Michael R Michaelides, Steven K Davidsen, Saul J Priceman, Jenny C Chang, Katrin Rhodes, Neil Shah, Theodore B Moore, Kathleen M Sakamoto, and Keith B Glaser ABT-869 a multi-targeted receptor tyrosine kinase inhibitor: inhibition of FLT3 phosphorylation and signaling in acute myeloid leukemia Blood First Edition Paper, prepublished online January 5, 2007; DOI 10.1182/blood-2006-06-029579 Blood, 5 January 2007, Vol. 0, No. 2007, pp. 200606029.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:17537
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:22 Feb 2010 17:38
Last Modified:03 Oct 2019 01:29

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