Ponatinib induces apoptosis in imatinib-resistant human mast cells by dephosphorylating mutant D816V KIT and silencing β-catenin signaling.

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.

• Authors: Bei Jin, Ke Ding, Jingxuan Pan
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 13 Issue 5 Pg. 1217-30 (May 2014) ISSN: 1538-8514 [Electronic] United States
• PMID: 24552773 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• Imidazoles
• Myeloid Cell Leukemia Sequence 1 Protein
• Protein Kinase Inhibitors
• Pyridazines
• TCF Transcription Factors
• beta Catenin
• ponatinib
• Cytochromes c
• Proto-Oncogene Proteins c-kit

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects, genetics)
• Apoptosis Regulatory Proteins (metabolism)
• Cell Line
• Cell Proliferation
• Cytochromes c (metabolism)
• Disease Models, Animal
• Drug Resistance
• Gene Expression Regulation (drug effects)
• Gene Silencing
• Humans
• Imidazoles (pharmacology)
• Male
• Mast Cells (drug effects, metabolism, pathology)
• Mastocytosis (genetics, metabolism, pathology)
• Mice
• Myeloid Cell Leukemia Sequence 1 Protein (genetics, metabolism)
• Phosphorylation (drug effects)
• Point Mutation
• Protein Binding
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-kit (genetics, metabolism)
• Pyridazines (pharmacology)
• Signal Transduction
• TCF Transcription Factors (metabolism)
• Wnt Signaling Pathway (drug effects)
• Xenograft Model Antitumor Assays
• beta Catenin (genetics, metabolism)