File(s) not publicly available

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

journal contribution
posted on 15.08.2018, 00:00 by KI Pishas, SJ Neuhaus, MT Clayer, AW Schreiber, DM Lawrence, M Perugini, RJ Whitfield, G Farshid, J Manavis, S Chryssidis
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. © 2013 AACR.

Funding

Category 2 - Other Public Sector Grants Category

History

Volume

74

Issue

3

Start Page

921

End Page

931

Number of Pages

12

eISSN

1538-7445

ISSN

0008-5472

Publisher

American Association for Cancer Research

Peer Reviewed

Yes

Open Access

Yes

External Author Affiliations

Sarcoma Research Group; Royal Adelaide Hospital; University of Adelaide; ACRF Cancer Genomics Facility; Queen Elizabeth Hospital; The Royal Melbourne Hospital

Era Eligible

Yes

Journal

Cancer Research

Usage metrics

Exports