Activity of a novel Aurora kinase inhibitor against the T315I mutant form of BCR-ABL: in vitro and in vivo studies.

Abstract

Despite promising results from clinical studies of ABL kinase inhibitors, a challenging problem that remains is the T315I mutation against which neither nilotinib nor dasatinib show significant activity. In the present study, we investigated the activity of a novel Aurora kinase inhibitor, VE-465, against leukemia cells expressing wild-type BCR-ABL or the T315I mutant form of BCR-ABL. We observed a dose-dependent reduction in the level of BCR-ABL autophosphorylation in VE-465-treated cells. Exposure to the combination of VE-465 and imatinib exerted an enhanced apoptotic effect in K562 cells. Combined treatment with VE-465 and imatinib caused more attenuation of the levels of phospho-AKT and c-Myc in K562 cells. Further, the isobologram indicated the synergistic effect of simultaneous exposure to VE-465 and imatinib in K562 cells. To assess the in vivo efficacy of VE-465, athymic nude mice were injected intravenously with BaF3 cells expressing wild-type BCR-ABL or the T315I mutant form. The vehicle-treated mice died of a condition resembling acute leukemia by 28 days; however, nearly all mice treated with VE-465 (75 mg/kg, twice daily; intraperitoneally for 14 days) survived for more than 56 days. Histopathological analysis of vehicle-treated mice revealed infiltration of the spleen. In contrast, histopathological analysis of organs from VE-465-treated mice demonstrated normal tissue architecture. Taken together, the present study shows that VE-465 exhibits a desirable therapeutic index that can reduce the in vivo growth of T315I mutant form and wild-type BCR-ABL-expressing cells in an efficacious manner.

• Authors: Daigo Akahane, Tetsuzo Tauchi, Seiichi Okabe, Kousuke Nunoda, Kazuma Ohyashiki
• Journal: Cancer science (Cancer Sci) Vol. 99 Issue 6 Pg. 1251-7 (Jun 2008) ISSN: 1349-7006 [Electronic] England
• PMID: 18429956 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Benzamides
• Enzyme Inhibitors
• Piperazines
• Pyrimidines
• tozasertib
• Imatinib Mesylate
• Protein-Tyrosine Kinases
• Fusion Proteins, bcr-abl
• Aurora Kinases
• Protein Serine-Threonine Kinases

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Apoptosis (drug effects)
• Aurora Kinases
• Benzamides
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation
• Colony-Forming Units Assay
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm
• Drug Therapy, Combination
• Enzyme Inhibitors (pharmacology)
• Female
• Fusion Proteins, bcr-abl (genetics, metabolism)
• Humans
• Imatinib Mesylate
• Immunoblotting
• Immunoprecipitation
• K562 Cells
• Leukemia, Experimental (drug therapy, enzymology, metabolism)
• Mice
• Mice, Nude
• Phosphorylation (drug effects)
• Piperazines (pharmacology, therapeutic use)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Pyrimidines (therapeutic use)
• Survival Rate