Antimyeloma activity of a multitargeted kinase inhibitor, AT9283, via potent Aurora kinase and STAT3 inhibition either alone or in combination with lenalidomide.

Abstract

PURPOSE:

Aurora kinases, whose expression is linked to genetic instability and cellular proliferation, are being investigated as novel therapeutic targets in multiple myeloma (MM). In this study, we investigated the preclinical activity of a small-molecule multitargeted kinase inhibitor, AT9283, with potent activity against Aurora kinase A, Aurora kinase B, and Janus kinase 2/3.

EXPERIMENTAL DESIGN:

We evaluated the in vitro antimyeloma activity of AT9283 alone and in combination with lenalidomide and the in vivo efficacy by using a xenograft mouse model of human MM.

RESULTS:

Our data showed that AT9283 induced cell-growth inhibition and apoptosis in MM. Studying the apoptosis mechanism of AT9283 in MM, we observed features consistent with both Aurora kinase A and Aurora kinase B inhibition, such as increase of cells with polyploid DNA content, decrease in phospho-histone H3, and decrease in phospho-Aurora A. Importantly, AT9283 also inhibited STAT3 tyrosine phosphorylation in MM cells. Genetic depletion of STAT3, Aurora kinase A, or Aurora kinase B showed growth inhibition of MM cells, suggesting a role of AT9283-induced inhibition of these molecules in the underlying mechanism of MM cell death. In vivo studies showed decreased MM cell growth and prolonged survival in AT9283-treated mice compared with controls. Importantly, combination studies of AT9283 with lenalidomide showed significant synergistic cytotoxicity in MM cells, even in the presence of bone marrow stromal cells. Enhanced cytotoxicity was associated with increased inhibition of phosphorylated STAT3 and phosphorylated extracellular signal-regulated kinase.

CONCLUSIONS:

Demonstration of in vitro and in vivo anti-MM activity of AT9283 provides the rationale for the clinical evaluation of AT9283 as monotherapy and in combination therapy for treating patients with MM.

• Authors: Loredana Santo, Teru Hideshima, Diana Cirstea, Madhavi Bandi, Erik A Nelson, Gullu Gorgun, Scott Rodig, Sonia Vallet, Samantha Pozzi, Kishan Patel, Christine Unitt, Matt Squires, Yiguo Hu, Dharminder Chauhan, Anuj Mahindra, Nikhil C Munshi, Kenneth C Anderson, Noopur Raje
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 10 Pg. 3259-71 (May 15 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21430070 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR.

Chemical References

• 1-cyclopropyl-3-(3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl)urea
• Benzimidazoles
• Protein Kinase Inhibitors
• STAT3 Transcription Factor
• Thalidomide
• Urea
• AURKA protein, human
• AURKB protein, human
• Aurka protein, mouse
• Aurkb protein, mouse
• Aurora Kinase A
• Aurora Kinase B
• Aurora Kinases
• Protein Serine-Threonine Kinases
• Lenalidomide

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Aurora Kinase A
• Aurora Kinase B
• Aurora Kinases
• Benzimidazoles (administration & dosage, therapeutic use)
• Cell Line, Tumor
• Drug Synergism
• Humans
• Lenalidomide
• Male
• Mice
• Mice, SCID
• Models, Biological
• Multiple Myeloma (drug therapy)
• Protein Kinase Inhibitors (administration & dosage, therapeutic use)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• STAT3 Transcription Factor (antagonists & inhibitors)
• Thalidomide (administration & dosage, analogs & derivatives)
• Treatment Outcome
• Urea (administration & dosage, analogs & derivatives, therapeutic use)
• Xenograft Model Antitumor Assays