TY - JOUR
T1 - A panel of isogenic human cancer cells suggests a therapeutic approach for cancers with inactivated p53
AU - Sur, Surojit
AU - Pagliarini, Raymond
AU - Bunz, Fred
AU - Rago, Carlo
AU - Diaz, Luis A.
AU - Kinzler, Kenneth W.
AU - Vogelstein, Bert
AU - Papadopoulos, Nickolas
PY - 2009/3/10
Y1 - 2009/3/10
N2 - 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 upregulation of polo-like kinase 1 (PLK1) as well as other genes controlling the G2/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.
AB - 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 upregulation of polo-like kinase 1 (PLK1) as well as other genes controlling the G2/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.
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U2 - 10.1073/pnas.0813333106
DO - 10.1073/pnas.0813333106
M3 - Article
C2 - 19225112
AN - SCOPUS:62649112876
SN - 0027-8424
VL - 106
SP - 3964
EP - 3969
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 10
ER -