Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/82418
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Type: | Journal article |
Title: | Nutlin-3a efficacy in sarcoma predicted by transcriptomic and epigenetic profiling |
Author: | Pishas, K. Neuhaus, S. Clayer, M. Schreiber, A. Lawrence, D. Perugini, M. Whitfield, R. Farshid, G. Manavis, J. Chryssidis, S. Mayo, B. Haycox, R. Ho, K. Brown, M. D'Andrea, R. Evdokiou, A. Thomas, D. Desai, J. Callen, D. Neilsen, P. |
Citation: | Cancer Research, 2014; 74(3):921-931 |
Publisher: | American Association for Cancer Research |
Issue Date: | 2014 |
ISSN: | 0008-5472 1538-7445 |
Statement of Responsibility: | Kathleen I. Pishas, Susan J. Neuhaus, Mark T. Clayer, Andreas W. Schreiber, David M. Lawrence, Michelle Perugini, Robert J. Whitfield, Gelareh Farshid, Jim Manavis, Steve Chryssidis, Bronwen J. Mayo, Rebecca C. Haycox, Kristen Ho, Michael P. Brown, Richard J. D'Andrea, Andreas Evdokiou, David M. Thomas, Jayesh Desai, David F. Callen and Paul M. Neilsen |
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. |
Keywords: | Cell Line, Tumor Humans Sarcoma Imidazoles Piperazines Cell Cycle Proteins Nuclear Proteins Antineoplastic Agents Prognosis Treatment Outcome Cluster Analysis Gene Expression Profiling Signal Transduction Apoptosis DNA Methylation Epigenesis, Genetic Gene Amplification Gene Expression Regulation, Neoplastic Drug Resistance, Neoplasm Polymorphism, Single Nucleotide Adolescent Adult Aged Aged, 80 and over Middle Aged Female Male Tumor Suppressor Protein p53 Proto-Oncogene Proteins c-mdm2 Young Adult Epigenomics Transcriptome |
Rights: | ©2013 AACR. |
DOI: | 10.1158/0008-5472.CAN-13-2424 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1048132 |
Published version: | http://dx.doi.org/10.1158/0008-5472.can-13-2424 |
Appears in Collections: | Aurora harvest Medicine publications |
Files in This Item:
File | Description | Size | Format | |
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hdl_82418.pdf | Accepted version | 2.13 MB | Adobe PDF | View/Open |
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