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Cancer Res ; 74(3): 921-31, 2014 Feb 01.
Article in English | MEDLINE | ID: mdl-24336067

ABSTRACT

Nutlin-3a is a small-molecule antagonist of p53/MDM2 that is being explored as a treatment for sarcoma. In this study, we examined the molecular mechanisms underlying the sensitivity of sarcomas to Nutlin-3a. In an ex vivo tissue explant system, we found that TP53 pathway alterations (TP53 status, MDM2/MDM4 genomic amplification/mRNA overexpression, MDM2 SNP309, and TP53 SNP72) did not confer apoptotic or cytostatic responses in sarcoma tissue biopsies (n = 24). Unexpectedly, MDM2 status did not predict Nutlin-3a sensitivity. RNA sequencing revealed that the global transcriptomic profiles of these sarcomas provided a more robust prediction of apoptotic responses to Nutlin-3a. Expression profiling revealed a subset of TP53 target genes that were transactivated specifically in sarcomas that were highly sensitive to Nutlin-3a. Of these target genes, the GADD45A promoter region was shown to be hypermethylated in 82% of wild-type TP53 sarcomas that did not respond to Nutlin-3a, thereby providing mechanistic insight into the innate ability of sarcomas to resist apoptotic death following Nutlin-3a treatment. Collectively, our findings argue that the existing benchmark biomarker for MDM2 antagonist efficacy (MDM2 amplification) should not be used to predict outcome but rather global gene expression profiles and epigenetic status of sarcomas dictate their sensitivity to p53/MDM2 antagonists.


Subject(s)
Antineoplastic Agents/pharmacology , Epigenesis, Genetic , Gene Expression Regulation, Neoplastic/drug effects , Imidazoles/pharmacology , Piperazines/pharmacology , Sarcoma/genetics , Transcriptome , Adolescent , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Apoptosis/genetics , Cell Cycle Proteins/genetics , Cell Line, Tumor , Cluster Analysis , DNA Methylation , Drug Resistance, Neoplasm/genetics , Epigenomics , Female , Gene Amplification , Gene Expression Profiling , Humans , Imidazoles/therapeutic use , Male , Middle Aged , Nuclear Proteins/genetics , Piperazines/therapeutic use , Polymorphism, Single Nucleotide , Prognosis , Proto-Oncogene Proteins c-mdm2/genetics , Sarcoma/drug therapy , Sarcoma/pathology , Signal Transduction/drug effects , Treatment Outcome , Tumor Suppressor Protein p53/genetics , Young Adult
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