Targets and effectors of the cellular response to aurora kinase inhibitor MK-0457 (VX-680) in imatinib sensitive and resistant chronic myelogenous leukemia.
MK-0457 inhibits aurora, BCR-ABL and other kinases and may be clinically active in imatinib resistant leukemia. To define mediators of MK-0457 responsiveness, kinase inhibitory profiles were examined in multiple cell models of imatinib sensitive and resistant disease. Aurora and BCR-ABL kinase inhibition were consistently measured at 20-100 nM and 2-10 microM MK-0457, respectively, but expression of T315I-BCR-ABL and overexpression of Lyn kinase reduced MK-0457 sensitivity. Aurora kinase inhibition was associated with cell cycle restriction and p53 induction and p53-null cells were far less responsive to MK-0457, requiring BCR-ABL inhibitory concentrations for apoptotic activity. In wild-type p53 expressing CML cells MK-0457 sensitivity was modulation by alterations in p53 levels through HDM-2 inhibition and gene silencing. MK-0457 suppressed aurora kinase activity and induced apoptosis in imatinib resistant clinical specimens expressing T315I and other BCR-ABL mutations without effecting BCR-ABL kinase activity. Together, these results suggest that MK-0457 apoptotic activity in CML cells is primarily associated with aurora kinase inhibition but can be altered by multiple molecular changes associated with disease progression or acquisition of imatinib resistance.
Donato
Nicholas J
NJ
University of Michigan, Department of Internal Medicine, 1500 E. Medical Center Dr., Room CC4306, Ann Arbor, MI 48109, USA. ndonato@med.umich.edu
Fang
Dexing
D
Sun
Hanshi
H
Giannola
Diane
D
Peterson
Luke F
LF
Talpaz
Moshe
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D064127:Aurora Kinases; D001549:Benzamides; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; 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