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• W2170723067 abstract "Abstract Gain-of-function mutations of membrane receptor tyrosine kinase KIT, especially gatekeeper D816V point mutation in KIT, render kinase autoactivation, disease progression, and poor prognosis. D816V KIT is found in approximately 80% of the patients with systemic mastocytosis, and is resistant to the first and second generations of tyrosine kinase inhibitors (TKI). The purpose of this investigation was aimed at exploring whether ponatinib (AP24534), a novel effective TKI against T315I Bcr-Abl, was active against D816V KIT. We discovered that ponatinib abrogated the phosphorylation of KIT harboring either V560G (sensitive to imatinib) or D816V mutation (resistant to imatinib) and the downstream signaling transduction. Ponatinib inhibited the growth of D816V KIT–expressing cells in culture and nude mouse xenografted tumor. Ponatinib triggered apoptosis by inducing the release of cytochrome c and AIF, downregulation of Mcl-1. Furthermore, ponatinib abrogated the phosphorylation of β-catenin at the site Y654, suppressed the translocation of β-catenin, and inhibited the transcription and DNA binding of TCF and the expression of its targets (e.g., AXIN2, c-MYC, and CCND1). Moreover, ponatinib was highly active against xenografted D816V KIT tumors in nude mice and significantly prolonged the survival of mice with aggressive systemic mastocytosis or mast cell leukemia by impeding the expansion and infiltration of mast cells with imatinib-resistant D814Y KIT. Our findings warrant a clinical trial of ponatinib in patients with systemic mastocytosis harboring D816V KIT. Mol Cancer Ther; 13(5); 1217–30. ©2014 AACR." @default.
• W2170723067 created "2016-06-24" @default.
• W2170723067 creator A5064691231 @default.
• W2170723067 creator A5071900138 @default.
• W2170723067 creator A5072601085 @default.
• W2170723067 date "2014-05-01" @default.
• W2170723067 modified "2023-10-12" @default.
• W2170723067 title "Ponatinib Induces Apoptosis in Imatinib-Resistant Human Mast Cells by Dephosphorylating Mutant D816V KIT and Silencing β-Catenin Signaling" @default.
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• W2170723067 doi "https://doi.org/10.1158/1535-7163.mct-13-0397" @default.
• W2170723067 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/24552773" @default.
• W2170723067 hasPublicationYear "2014" @default.
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