Crenolanib is active against models of drug-resistant FLT3-ITD−positive acute myeloid leukemia

FLT3 kinase internal tandem duplication (ITD) mutations are common in acute myeloid leukemia (AML) and are associated with poor clinical outcomes. Although initial responses to FLT3 tyrosine kinase inhibitors (TKIs) are observed in FLT3-ITD−positive patients, subsequent relapse often occurs upon acq...

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Veröffentlicht in:Blood 2013-11, Vol.122 (22), p.3607-3615
Hauptverfasser: Zimmerman, Eric I., Turner, David C., Buaboonnam, Jassada, Hu, Shuiying, Orwick, Shelley, Roberts, Michael S., Janke, Laura J., Ramachandran, Abhijit, Stewart, Clinton F., Inaba, Hiroto, Baker, Sharyn D.
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container_end_page 3615
container_issue 22
container_start_page 3607
container_title Blood
container_volume 122
creator Zimmerman, Eric I.
Turner, David C.
Buaboonnam, Jassada
Hu, Shuiying
Orwick, Shelley
Roberts, Michael S.
Janke, Laura J.
Ramachandran, Abhijit
Stewart, Clinton F.
Inaba, Hiroto
Baker, Sharyn D.
description FLT3 kinase internal tandem duplication (ITD) mutations are common in acute myeloid leukemia (AML) and are associated with poor clinical outcomes. Although initial responses to FLT3 tyrosine kinase inhibitors (TKIs) are observed in FLT3-ITD−positive patients, subsequent relapse often occurs upon acquisition of secondary FLT3 kinase domain (KD) mutations, primarily at residues D835 and F691. Using biochemical assays, we determined that crenolanib, a novel TKI, demonstrates type I properties and is active against FLT3 containing ITD and/or D835- or F691-activating mutations. Potent activity was observed in FLT3-ITD−positive AML cell lines. Crenolanib delayed the outgrowth of MV4-11 cells in a xenograft mouse model, whereas in combination with the type II TKI sorafenib, a significant decrease in leukemic burden (P < .001) and prolonged survival (P < .01) was observed compared with either type I or II TKI alone. Crenolanib was active against Ba/F3 cells harboring FLT3-ITD and secondary KD mutations and sorafenib-resistant MOLM-13 cells containing FLT3-ITD/D835Y both in vitro and in vivo. In addition, crenolanib inhibited drug-resistant AML primary blasts with FLT3-ITD and D835H/Y mutations. These preclinical data demonstrate that crenolanib is effective against FLT3-ITD containing secondary KD mutations, suggesting that crenolanib may be a useful therapeutic agent for TKI-naive and drug-resistant FLT3-ITD−positive AML. •The tyrosine kinase inhibitor crenolanib has type 1 inhibitor properties and has potent activity against FLT3-activating mutations.•Crenolanib is active in vitro and in vivo against FLT3 inhibitor-resistant FLT3-ITD/D835 mutations.
doi_str_mv 10.1182/blood-2013-07-513044
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subjects Animals
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - pharmacokinetics
Antineoplastic Agents - therapeutic use
Benzimidazoles - administration & dosage
Benzimidazoles - pharmacokinetics
Benzimidazoles - therapeutic use
Cell Line, Tumor
Cell Survival - drug effects
Drug Resistance, Neoplasm
Drug Synergism
Female
fms-Like Tyrosine Kinase 3 - antagonists & inhibitors
fms-Like Tyrosine Kinase 3 - genetics
Humans
Leukemia, Myeloid, Acute - drug therapy
Leukemia, Myeloid, Acute - enzymology
Leukemia, Myeloid, Acute - genetics
Male
Mice
Mice, Inbred NOD
Mice, SCID
Mutation
Myeloid Neoplasia
Niacinamide - administration & dosage
Niacinamide - analogs & derivatives
Phenylurea Compounds - administration & dosage
Piperidines - administration & dosage
Piperidines - pharmacokinetics
Piperidines - therapeutic use
Protein Kinase Inhibitors - administration & dosage
Protein Kinase Inhibitors - pharmacokinetics
Protein Kinase Inhibitors - therapeutic use
Sorafenib
Tandem Repeat Sequences
Xenograft Model Antitumor Assays
title Crenolanib is active against models of drug-resistant FLT3-ITD−positive acute myeloid leukemia
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