Abstract
AZD1152 is a highly selective Aurora B kinase inhibitor currently undergoing Phase I and II clinical evaluation in patients with acute myelogenous leukemia and advanced solid malignancies. We have established two AZD1152-resistant cell lines from SW620 colon and MiaPaCa pancreatic carcinoma lines, which are >100-fold resistant to the active metabolite of AZD1152, AZD1152 HQPA and interestingly, cross-resistant to the pan-Aurora kinase inhibitor, VX-680/MK0457. Using whole-genome microarray analysis and comparative genomic hybridization, we were able to identify MDR1 and BCRP as the causative genes that underlie AZD1152 HQPA-resistance in these models. Furthermore, the upregulation of either of these genes is sufficient to render in vivo tumor growth insensitive to AZD1152. Finally, the upregulation of MDR1 or BCRP is predictive of tumor cell sensitivity to this agent, both in vitro and in vivo. The data provide a genetic basis for resistance to Aurora kinase inhibitors, which could be utilized to predict clinical response to therapy.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics*
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters / genetics*
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ATP-Binding Cassette Transporters / metabolism
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Animals
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Antineoplastic Agents / pharmacology*
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Aurora Kinase B
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Aurora Kinases
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Cell Line, Tumor
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Cell Survival / drug effects
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Comparative Genomic Hybridization
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Dose-Response Relationship, Drug
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Drug Resistance, Neoplasm / genetics*
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Gene Expression Profiling / methods
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Gene Expression Regulation, Neoplastic*
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Humans
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Inhibitory Concentration 50
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Mice
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Mice, SCID
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Neoplasm Proteins / genetics*
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Neoplasm Proteins / metabolism
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Oligonucleotide Array Sequence Analysis
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Organophosphates / pharmacology*
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Piperazines / pharmacology
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Protein Kinase Inhibitors / pharmacology*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Quinazolines / pharmacology*
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RNA Interference
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RNA, Small Interfering / metabolism
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Time Factors
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Up-Regulation
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Xenograft Model Antitumor Assays
Substances
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2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate
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ABCB1 protein, human
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ABCG2 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters
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Antineoplastic Agents
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Neoplasm Proteins
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Organophosphates
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Piperazines
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Protein Kinase Inhibitors
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Quinazolines
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RNA, Small Interfering
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tozasertib
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AURKB protein, human
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Aurkb protein, mouse
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Aurora Kinase B
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Aurora Kinases
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Protein Serine-Threonine Kinases