Activity of a novel Aurora kinase inhibitor against the T315I mutant form of BCR-ABL: in vitro and in vivo studies.
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.
Akahane
Daigo
D
First Department of Internal Medicine, Tokyo Medical University, Shinjuku-ku, Tokyo 160-0023, Japan.
Tauchi
Tetsuzo
T
Okabe
Seiichi
S
Nunoda
Kousuke
K
Ohyashiki
Kazuma
K
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D064127:Aurora Kinases; D001549:Benzamides; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003114:Colony-Forming Units Assay; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D015151:Immunoblotting; D047468:Immunoprecipitation; D020014:K562 Cells; D007942:Leukemia, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000627:therapeutic use; D015996:Survival Rate; D003521:Cyclopropanes; D011720:Pyrazoles
D000970:Antineoplastic Agents; D064127:Aurora Kinases; D001549:Benzamides; D004791:Enzyme Inhibitors; D016044:Fusion Proteins, bcr-abl; D000068877:Imatinib Mesylate; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011743:Pyrimidines; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles