Nutlin-3a Efficacy in Sarcoma Predicted by Transcriptomic and Epigenetic Profiling
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, Paul M Neilsen
CANCER RESEARCH | AMER ASSOC CANCER RESEARCH | Published : 2014
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 prof..View full abstract
Awarded by Cancer Australia
This study was supported by the ASSG Sarcoma Research Award funded through the Rainbows for Kate Foundation in memory of Tom Wood, Florey Medical Research Foundation, Royal Adelaide Hospital Research Foundation, Freemasons Trevor Prescott Memorial Scholarship, Cancer Australia (APP1034715), and Cure Cancer Australia Foundation. M. Perugini acknowledges financial contributions from the Fred Shahin Early-Career Fellowship.