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Proc Natl Acad Sci U S A. 2009 Mar 10;106(10):3964-9. doi: 10.1073/pnas.0813333106. Epub 2009 Feb 18.

A panel of isogenic human cancer cells suggests a therapeutic approach for cancers with inactivated p53.

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  • 1The Howard Hughes Medical Institute and The Ludwig Center for Cancer Genetics and Therapeutics, Baltimore, MD 21231, USA.

Abstract

Through targeted homologous recombination, we developed a panel of matched colorectal cancer cell lines that differ only with respect to their endogenous TP53 status. We then used these lines to define the genes whose expression was altered after DNA damage induced by ionizing radiation. Transcriptome analyses revealed a consistent up-regulation of polo-like kinase 1 (PLK1) as well as other genes controlling the G(2)/M transition in the cells whose TP53 genes were inactivated compared with those with WT TP53 genes. This led to the hypothesis that the viability of stressed cells without WT TP53 depended on PLK1. This hypothesis was validated by demonstrating that stressed cancer cells without WT TP53 alleles were highly sensitive to PLK1 inhibitors, both in vivo and in vitro.

PMID:
19225112
[PubMed - indexed for MEDLINE]
PMCID:
PMC2656188
Free PMC Article
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