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Ref Type Journal Article
PMID (22293494)
Authors Nair JS, Ho AL, Schwartz GK
Title The induction of polyploidy or apoptosis by the Aurora A kinase inhibitor MK8745 is p53-dependent.
Journal Vol Issue Date Pages Journal Short Title
Cell cycle (Georgetown, Tex.) 11 4 2012 Feb 15 807-17 Cell Cycle
URL
Abstract Text Aurora kinases are mitotic serine/threonine protein kinases and are attractive novel targets for anticancer therapy. Many small-molecule inhibitors of Aurora kinases are currently undergoing clinical trials. Aurora A kinase is essential for successful mitotic transition. MK8745 is a novel and selective small-molecule inhibitor of Aurora A kinase. MK8745 induced apoptotic cell death in a p53-dependent manner when tested in vitro in cell lines of multiple lineages. Cells expressing wild-type p53 showed a short delay in mitosis followed by cytokinesis, resulting in 2N cells along with apoptosis. However, cells lacking or with mutant p53 resulted in a prolonged arrest in mitosis followed by endoreduplication and polyploidy. Cytokinesis was completely inhibited in p53-deficient cells, as observed by the absence of 2N cell population. The induction of apoptosis in p53-proficient cells was associated with activation of caspase 3 and release of cytochrome c but was independent of p21. Exposure of p53 wild-type cells to MK8745 resulted in the induction of p53 phosphorylation (ser15) and an increase in p53 protein expression. p53-dependent apoptosis by MK8745 was further confirmed in HCT 116 p53(-/-) cells transfected with wild-type p53. Transient knockdown of Aurora A by specific siRNA recapitulated these p53- dependent effects, with greater percent induction of apoptosis in p53 wild-type cells. In conclusion, our studies show p53 as a determining factor for induction of apoptosis vs. polyploidy upon inhibition of Aurora A.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
TP53 del colorectal cancer predicted - sensitive MK-8745 Preclinical - Cell culture Actionable In a preclinical study, MK-8745 treatment resulted in polyploidy in TP53-null colorectal cancer cells in culture (PMID: 22293494). 22293494
TP53 wild-type colorectal cancer predicted - sensitive MK-8745 Preclinical - Cell culture Actionable In a preclinical study, MK-8745 treatment resulted in apoptosis in Tp53 wild-type colorectal cancer cells in culture (PMID: 22293494). 22293494