Ponatinib efficiently kills imatinib-resistant chronic eosinophilic leukemia cells harboring gatekeeper mutant T674I FIP1L1-PDGFRα: roles of Mcl-1 and β-cateninReport as inadecuate




Ponatinib efficiently kills imatinib-resistant chronic eosinophilic leukemia cells harboring gatekeeper mutant T674I FIP1L1-PDGFRα: roles of Mcl-1 and β-catenin - Download this document for free, or read online. Document in PDF available to download.

Molecular Cancer

, 13:17

First Online: 28 January 2014Received: 23 August 2013Accepted: 08 January 2014DOI: 10.1186-1476-4598-13-17

Cite this article as: Jin, Y., Ding, K., Li, H. et al. Mol Cancer 2014 13: 17. doi:10.1186-1476-4598-13-17

Abstract

BackgroundT674I FIP1L1-PDGFRα 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-PDGFRα 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-PDGFRα. The purpose of this study was to examine the effect of ponatinib on T674I FIP1L1-PDGFRα.

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

ResultsMolecular docking analysis revealed that ponatinib could bind to the DFG Asp-Phe-Gly-out state of T674I PDGFRα. Ponatinib potently inhibited the phosphorylation of WT and T674I FIP1L1-PDGFRα and their downstream signaling molecules e.g., Stat3, Stat5. Ponatinib strikingly inhibited the growth of both WT and T674I FIP1L1-PDGFRα-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 β-catenin to decrease its stability and pro-survival functions. In vivo, ponatinib abrogated the growth of xenografted BaF3-T674I FIP1L1-PDGFRα cells in nude mice.

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

KeywordsPDGFRα T674I mutant Tyrosine kinase inhibitor Imatinib Resistance Ponatinib Apoptosis AbbreviationsPDGFRαPlatelet-derived growth factor receptor α

FIP1L1-PDGFRαFIP1-like 1-PDGFRα

CELchronic eosinophilic leukemia

EMSAelectrophoretic mobility shift assay

TCF-LEFT cell factor-lymphoid enhancer factor

CHXcycloheximide

APCadenomatous polyposis coli

GSK3βkinase glycogen synthase kinase 3β.

Electronic supplementary materialThe online version of this article doi:10.1186-1476-4598-13-17 contains supplementary material, which is available to authorized users.

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Author: Yanli Jin - Ke Ding - Honglin Li - Mengzhu Xue - Xiaoke Shi - Chengyan Wang - Jingxuan Pan

Source: https://link.springer.com/







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