Ponatinib efficiently kills imatinib-resistant chronic eosinophilic leukemia cells harboring gatekeeper mutant T674I FIP1L1-PDGFR?: roles of Mcl-1 and ?-catenin.

ABSTRACT:

Background

T674I FIP1L1-PDGFR? in a subset of chronic eosinophilic leukemia (CEL) is a gatekeeper mutation that is resistant to many tyrosine kinase inhibitors (TKIs) (e.g., imatinib, nilotinib and dasatinib), similar to T315I Bcr-Abl. Therefore, novel TKIs effective against T674I FIP1L1-PDGFR? are needed. Ponatinib (AP24534) is a novel orally bioavailable TKI against T315I Bcr-Abl, but it is not clear whether ponatinib is effective against T674I FIP1L1-PDGFR?. The purpose of this study was to examine the effect of ponatinib on T674I FIP1L1-PDGFR?.

Methods

Molecular docking analysis in silico was performed. The effects of ponatinib on PDGFR? signaling pathways, apoptosis and cell cycling were examined in EOL-1, BaF3 cells expressing either wild type (WT) or T674I FIP1L1-PDGFR?. The in vivo antitumor activity of ponatinib was evaluated with xenografted BaF3-T674I FIP1L1-PDGFR? cells in nude mice models.

Results

Molecular docking analysis revealed that ponatinib could bind to the DFG (Asp-Phe-Gly)-out state of T674I PDGFR?. Ponatinib potently inhibited the phosphorylation of WT and T674I FIP1L1-PDGFR? and their downstream signaling molecules (e.g., Stat3, Stat5). Ponatinib strikingly inhibited the growth of both WT and T674I FIP1L1-PDGFR?-carrying CEL cells (IC50: 0.004-2.5 nM). It induced apoptosis in CEL cells with caspase-3-dependent cleavage of Mcl-1, and inhibited tyrosine phosphorylation of ?-catenin to decrease its stability and pro-survival functions. In vivo, ponatinib abrogated the growth of xenografted BaF3-T674I FIP1L1-PDGFR? cells in nude mice.

Conclusions

Ponatinib is a pan-FIP1L1-PDGFR? inhibitor, and clinical trials are warranted to investigate its efficacy in imatinib-resistant CEL.

SUBMITTER: Jin Y 

PROVIDER: S-EPMC3928078 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature