The FLT3 internal tandem duplication mutation is a secondary target of the aurora B kinase inhibitor AZD1152-HQPA in acute myelogenous leukemia cells.

Abstract

Aurora kinases play an essential role in orchestrating chromosome alignment, segregation, and cytokinesis during mitotic progression and both aurora-A and B are frequently overexpressed in a variety of human malignancies. In this study, we report the effects of AZD1152-HQPA, a highly selective inhibitor of aurora-B kinase, in acute myeloid leukemia (AML) cell lines and primary samples. We show that AZD1152-HQPA inhibits the phosphorylation of Histone H3 (pHH3) on serine 10 resulting in polyploid cells, apoptosis, and loss of viability in a panel of AML cell lines. We also show that AZD1152-HQPA sensitivity in our cell lines is irrespective of p53 status and the FLT3-ITD-expressing MOLM-13 and MV4-11 cell lines are particularly sensitive to AZD1152-HQPA. Internal tandem duplications (ITD) within the FLT3 tyrosine kinase receptor are found in approximately 25% of AML patients and are associated with a poor prognosis. Here, we report that AZD1152-HQPA directly targets phosphorylated FLT3 along with inhibiting its downstream target phospho-signal transducer and activator of transcription 5 (STAT5) in the FLT3-ITD cell lines. We show pHH3 expression in primary AML blasts and its inhibition by AZD1152-HQPA at low doses in all of our primary samples tested. AZD1152-HQPA inhibits the clonogenic potential of primary AML samples, with FLT3-ITD samples being the most sensitive (P = 0.029). FLT3-ITD primary samples are also more sensitive to pHH3 inhibition (P = 0.022) and are particularly sensitive to pSTAT5 downregulation after treatment with AZD1152-HQPA compared with FLT3 wild-type samples (P = 0.007). We conclude that mutant FLT3 is a secondary target of AZD1152-HQPA and that FLT3-ITD primary samples are particularly sensitive to the drug.

• Authors: Martin Grundy, Claire Seedhouse, Shilli Shang, Jaineeta Richardson, Nigel Russell, Monica Pallis
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 9 Issue 3 Pg. 661-72 (Mar 2010) ISSN: 1538-8514 [Electronic] United States
• PMID: 20159992 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Histones
• Protein Kinase Inhibitors
• Quinazolines
• AZD 1152-HQPA
• FLT3 protein, human
• fms-Like Tyrosine Kinase 3
• AURKB protein, human
• Aurora Kinase B
• Aurora Kinases
• Protein Serine-Threonine Kinases

Topics

• Antineoplastic Agents (administration & dosage, pharmacology)
• Apoptosis (drug effects)
• Aurora Kinase B
• Aurora Kinases
• Cell Survival (drug effects)
• Drug Delivery Systems
• Drug Evaluation, Preclinical
• Gene Expression Regulation, Leukemic (drug effects)
• Histones (genetics, metabolism)
• Humans
• Leukemia, Myeloid, Acute (drug therapy, genetics, pathology)
• Mutagenesis, Insertional (physiology)
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (administration & dosage, pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Quinazolines (administration & dosage, pharmacology)
• Tandem Repeat Sequences (genetics)
• Tumor Cells, Cultured
• U937 Cells
• fms-Like Tyrosine Kinase 3 (genetics, metabolism)