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|Ref Type||Journal Article|
|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||Cell cycle (Georgetown, Tex.)|
|Date||2012 Feb 15|
|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.|
|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||TC-A2317||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|