PMID- 20007803
OWN - NLM
STAT- MEDLINE
DCOM- 20100326
LR  - 20211203
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 115
IP  - 7
DP  - 2010 Feb 18
TI  - FLT3-mutant allelic burden and clinical status are predictive of response to FLT3 
      inhibitors in AML.
PG  - 1425-32
LID - 10.1182/blood-2009-09-242859 [doi]
AB  - We examined 6 different FMS-like tyrosine kinase-3 (FLT3) inhibitors 
      (lestaurtinib, midostaurin, AC220, KW-2449, sorafenib, and sunitinib) for potency 
      against mutant and wild-type FLT3, as well as for cytotoxic effect against a 
      series of primary blast samples obtained from patients with acute myeloid 
      leukemia (AML) harboring internal tandem duplication (FLT3/ITD) mutations. We 
      found that inhibition of FLT3 autophosphorylation in a FLT3/ITD specimen does not 
      always induce cell death, suggesting that some FLT3/ITD AML may not be addicted 
      to FLT3 signaling. Relapsed samples and samples with a high mutant allelic burden 
      were more likely to be responsive to cytotoxicity from FLT3 inhibition compared 
      with the samples obtained at diagnosis or those with a low mutant allelic burden. 
      These FLT3 inhibitors varied to a considerable degree in their selectivity for 
      FLT3, and this selectivity influenced the cytotoxic effect. These results have 
      important implications for the potential therapeutic use of FLT3 inhibitors in 
      that patients with newly diagnosed FLT3-mutant AML might be less likely to 
      respond clinically to highly selective FLT3 inhibition.
FAU - Pratz, Keith W
AU  - Pratz KW
AD  - Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, 
      MD 21231, USA.
FAU - Sato, Takashi
AU  - Sato T
FAU - Murphy, Kathleen M
AU  - Murphy KM
FAU - Stine, Adam
AU  - Stine A
FAU - Rajkhowa, Trivikram
AU  - Rajkhowa T
FAU - Levis, Mark
AU  - Levis M
LA  - eng
GR  - P50 CA100632/CA/NCI NIH HHS/United States
GR  - R01 CA128864/CA/NCI NIH HHS/United States
GR  - R01 CA128864-04/CA/NCI NIH HHS/United States
GR  - SPORE P50 CA100632-06/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20091210
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Benzenesulfonates)
RN  - 0 (Benzothiazoles)
RN  - 0 (Carbazoles)
RN  - 0 (Furans)
RN  - 0 (Indazoles)
RN  - 0 (Indoles)
RN  - 0 (KW 2449)
RN  - 0 (Phenylurea Compounds)
RN  - 0 (Piperazines)
RN  - 0 (Pyridines)
RN  - 0 (Pyrroles)
RN  - 25X51I8RD4 (Niacinamide)
RN  - 7LA4O6Q0D3 (quizartinib)
RN  - 9ZOQ3TZI87 (Sorafenib)
RN  - DO989GC5D1 (lestaurtinib)
RN  - EC 2.7.10.1 (FLT3 protein, human)
RN  - EC 2.7.10.1 (fms-Like Tyrosine Kinase 3)
RN  - H88EPA0A3N (Staurosporine)
RN  - ID912S5VON (midostaurin)
RN  - V99T50803M (Sunitinib)
SB  - IM
MH  - Alleles
MH  - Antineoplastic Agents/*pharmacology
MH  - Benzenesulfonates/pharmacology
MH  - Benzothiazoles/pharmacology
MH  - Carbazoles/*pharmacology
MH  - Cell Death/drug effects
MH  - Cell Line, Tumor
MH  - Drug Resistance, Neoplasm/genetics
MH  - Furans
MH  - Humans
MH  - Indazoles/pharmacology
MH  - Indoles/pharmacology
MH  - Leukemia, Myeloid, Acute/*drug therapy/*genetics
MH  - Mutation
MH  - Niacinamide/analogs & derivatives
MH  - Phenylurea Compounds/pharmacology
MH  - Phosphorylation/drug effects
MH  - Piperazines/pharmacology
MH  - Pyridines/pharmacology
MH  - Pyrroles/pharmacology
MH  - Sorafenib
MH  - Staurosporine/analogs & derivatives/pharmacology
MH  - Sunitinib
MH  - fms-Like Tyrosine Kinase 3/*antagonists & inhibitors/*genetics
PMC - PMC2826764
EDAT- 2009/12/17 06:00
MHDA- 2010/03/27 06:00
PMCR- 2011/02/18
CRDT- 2009/12/17 06:00
PHST- 2009/12/17 06:00 [entrez]
PHST- 2009/12/17 06:00 [pubmed]
PHST- 2010/03/27 06:00 [medline]
PHST- 2011/02/18 00:00 [pmc-release]
AID - S0006-4971(20)56754-2 [pii]
AID - 2009/242859 [pii]
AID - 10.1182/blood-2009-09-242859 [doi]
PST - ppublish
SO  - Blood. 2010 Feb 18;115(7):1425-32. doi: 10.1182/blood-2009-09-242859. Epub 2009 
      Dec 10.