Sensitivity of Cancer Cells to Plk1 Inhibitor GSK461364A Is Associated with Loss of p53 Function and Chromosome Instability

Degenhardt, Y., Greshock, J., Laquerre, S., Gilmartin, A. G., Jing, J., Richter, M., Zhang, X., Bleam, M., Halsey, W., Hughes, A., Moy, C., Liu-Sullivan, N., Powers, S., Bachman, K., Jackson, J., Weber, B., Wooster, R. (July 2010) Sensitivity of Cancer Cells to Plk1 Inhibitor GSK461364A Is Associated with Loss of p53 Function and Chromosome Instability. Molecular Cancer Therapeutics, 9 (7). pp. 2079-2089. ISSN 1535-7163

URL: http://www.ncbi.nlm.nih.gov/pubmed/20571075
DOI: 10.1158/1535-7163.MCT-10-0095

Abstract

Polo-like kinases are a family of serine threonine kinases that are critical regulators of cell cycle progression and DNA damage response. Predictive biomarkers for the Plk1-selective inhibitor GSK461364A were identified by comparing the genomics and genetics of a panel of human cancer cell lines with their response to a drug washout followed by an outgrowth assay. In this assay, cell lines that have lost p53 expression or carry mutations in the TP53 gene tended to be more sensitive to GSK461364A. These more sensitive cell lines also had increased levels of chromosome instability, a characteristic associated with loss of p53 function. Further mechanistic studies showed that p53 wild-type (WT) and not mutant cells can activate a postmitotic tetraploidy checkpoint and arrest at pseudo-G(1) state after GSK461364A treatment. RNA silencing of WT p53 increased the antiproliferative activity of GSK461364A. Furthermore, silencing of p53 or p21/CDKN1A weakened the tetraploidy checkpoint in cells that survived mitotic arrest and mitotic slippage. As many cancer therapies tend to be more effective in p53 WT patients, the higher sensitivity of p53-deficient tumors toward GSK461364A could potentially offer an opportunity to treat tumors that are refractory to other chemotherapies as well as early line therapy for these genotypes. Mol Cancer Ther; 9(7); OF1-11. (c)2010 AACR.

Item Type: Paper
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > RNA silencing
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes
organism description > animal > mammal > primates > hominids > human
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase > tyrosine kinase
CSHL Authors:
Communities: CSHL labs > Powers lab
CSHL Cancer Center Shared Resources > DNA Sequencing Service
CSHL Cancer Center Shared Resources > Microarray Service
Depositing User: CSHL Librarian
Date: July 2010
Date Deposited: 29 Sep 2011 20:33
Last Modified: 26 Dec 2014 20:52
Related URLs:
URI: http://repository.cshl.edu/id/eprint/15398

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