RRC ID 64539
Author Chen F, Ishikawa Y, Akashi A, Naoe T, Kiyoi H.
Title Co-expression of wild-type FLT3 attenuates the inhibitory effect of FLT3 inhibitor on FLT3 mutated leukemia cells.
Journal Oncotarget
Abstract FLT3 mutation is found in about 30% of acute myeloid leukemia (AML) patients and is associated with a poor prognosis. Several FLT3 inhibitors are undergoing investigation, while their clinical efficacies were lower than expected and several resistant mechanisms to FLT3 inhibitors have been demonstrated. Although most AML cells harboring FLT3 mutation co-express wild-type (Wt)-FLT3, it is not fully understood how Wt-FLT3 expression is associated with the resistance to FLT3 inhibitors. In this study, we elucidated a resistant mechanism by which FL-dependent Wt-FLT3 activation reduced inhibitory effects of FLT3 inhibitors. We demonstrated that FL-stimulation much more strongly reduced growth inhibitory effects of FLT3 inhibitors on Wt- and mutant-FLT3 co-expressing cells than sole mutant-FLT3 expressing cells both in vitro and in vivo. It was also confirmed that FL impaired the anti-leukemia effects of FLT3 inhibitors on primary AML cells. We elucidated that FL impeded the inhibitory effects of FLT3 inhibitors mainly through the activation of Wt-FLT3, but not mutated FLT3, in the Wt- and ITD-FLT3 co-expressing cells. Furthermore, FL-induced activation of Wt-FLT3-MAPK axis was the dominant pathway for the resistance, and the glycosylation of Wt-FLT3 was also vital for FL-dependent kinase activation and following resistance to FLT3 inhibitors. Thus, we clarified the importance of co-expressing Wt-FLT3 in resistance to FLT3 inhibitors. These findings provide us with important implications for clinical application and new strategies to improve clinical outcomes of FLT3 inhibitors.
Volume 7(30)
Pages 47018-47032
Published 2016-7-26
DOI 10.18632/oncotarget.10147
PII 10147
PMID 27331411
PMC PMC5216920
MeSH Animals Antineoplastic Agents / pharmacology* Antineoplastic Agents / therapeutic use Bone Marrow / pathology Cell Line, Tumor Drug Resistance, Neoplasm* Humans Leukemia, Myeloid, Acute / drug therapy* Leukemia, Myeloid, Acute / genetics Leukemia, Myeloid, Acute / pathology MAP Kinase Signaling System Membrane Proteins / metabolism* Mice Mice, Inbred NOD Mice, SCID Mutation Primary Cell Culture Protein Domains / genetics Protein Kinase Inhibitors / pharmacology* Protein Kinase Inhibitors / therapeutic use Tandem Repeat Sequences Xenograft Model Antitumor Assays fms-Like Tyrosine Kinase 3 / antagonists & inhibitors* fms-Like Tyrosine Kinase 3 / genetics fms-Like Tyrosine Kinase 3 / metabolism*
IF 5.168
Resource
Human and Animal Cells 32Dcl3(RCB1377)