Nutlin-3a efficacy in sarcoma predicted by transcriptomic and epigenetic profiling

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dc.contributor.authorPishas, K.
dc.contributor.authorNeuhaus, S.
dc.contributor.authorClayer, M.
dc.contributor.authorSchreiber, A.
dc.contributor.authorLawrence, D.
dc.contributor.authorPerugini, M.
dc.contributor.authorWhitfield, R.
dc.contributor.authorFarshid, G.
dc.contributor.authorManavis, J.
dc.contributor.authorChryssidis, S.
dc.contributor.authorMayo, B.
dc.contributor.authorHaycox, R.
dc.contributor.authorHo, K.
dc.contributor.authorBrown, M.
dc.contributor.authorD'Andrea, R.
dc.contributor.authorEvdokiou, A.
dc.contributor.authorThomas, D.
dc.contributor.authorDesai, J.
dc.contributor.authorCallen, D.
dc.contributor.authorNeilsen, P.
dc.date.issued2014
dc.description.abstractNutlin-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.
dc.description.statementofresponsibilityKathleen 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
dc.identifier.citationCancer Research, 2014; 74(3):921-931
dc.identifier.doi10.1158/0008-5472.CAN-13-2424
dc.identifier.issn0008-5472
dc.identifier.issn1538-7445
dc.identifier.orcidNeuhaus, S. [0000-0001-6520-6892]
dc.identifier.orcidSchreiber, A. [0000-0002-9081-3405]
dc.identifier.orcidLawrence, D. [0000-0001-5464-5830]
dc.identifier.orcidFarshid, G. [0000-0002-2056-0561]
dc.identifier.orcidManavis, J. [0000-0001-7381-7781] [0000-0003-1268-561X]
dc.identifier.orcidBrown, M. [0000-0002-5796-1932] [0000-0002-6678-1407]
dc.identifier.orcidEvdokiou, A. [0000-0001-8321-9806]
dc.identifier.orcidCallen, D. [0000-0002-6189-9991]
dc.identifier.urihttp://hdl.handle.net/2440/82418
dc.language.isoen
dc.publisherAmerican Association for Cancer Research
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1048132
dc.relation.isreplacedby2440/90445
dc.relation.isreplacedbyhttp://hdl.handle.net/2440/90445
dc.rights©2013 AACR.
dc.source.urihttps://doi.org/10.1158/0008-5472.can-13-2424
dc.subjectCell Line, Tumor
dc.subjectHumans
dc.subjectSarcoma
dc.subjectImidazoles
dc.subjectPiperazines
dc.subjectCell Cycle Proteins
dc.subjectNuclear Proteins
dc.subjectAntineoplastic Agents
dc.subjectPrognosis
dc.subjectTreatment Outcome
dc.subjectCluster Analysis
dc.subjectGene Expression Profiling
dc.subjectSignal Transduction
dc.subjectApoptosis
dc.subjectDNA Methylation
dc.subjectEpigenesis, Genetic
dc.subjectGene Amplification
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectDrug Resistance, Neoplasm
dc.subjectPolymorphism, Single Nucleotide
dc.subjectAdolescent
dc.subjectAdult
dc.subjectAged
dc.subjectAged, 80 and over
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectMale
dc.subjectTumor Suppressor Protein p53
dc.subjectProto-Oncogene Proteins c-mdm2
dc.subjectYoung Adult
dc.subjectEpigenomics
dc.subjectTranscriptome
dc.titleNutlin-3a efficacy in sarcoma predicted by transcriptomic and epigenetic profiling
dc.typeJournal article
pubs.publication-statusPublished

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