A panel of isogenic human cancer cells suggests a therapeutic approach for cancers with inactivated p53.
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.
Sur
Surojit
S
The Howard Hughes Medical Institute and The Ludwig Center for Cancer Genetics and Therapeutics, Baltimore, MD 21231, USA.
Pagliarini
Raymond
R
Bunz
Fred
F
Rago
Carlo
C
Diaz
Luis A
LA
Kinzler
Kenneth W
KW
Vogelstein
Bert
B
Papadopoulos
Nickolas
N
D000483:Alleles; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D020869:Gene Expression Profiling; D018390:Gene Targeting; D005838:Genotype; D006801:Humans; D007093:Imidazoles / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000473:pathology* / Q000628:therapy*; D010879:Piperazines / Q000378:metabolism; D011621:Pteridines / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C518477:BI 2536; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007093:Imidazoles; D010879:Piperazines; D011621:Pteridines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3