Abstract 3436: Integrated profiling of p53 wild-type cell lines identifies differentially responsive populations and a gene expression signature that predicts sensitivity to SAR405838, a potent and selective disruptor of the p53-MDM2 interaction.
Authors: Watters James , Rowley Steve , Debussche Laurent 
Published: August 2014

The tumor suppressor protein p53 functions at the center of a complex biological network that translates diverse stress signals into cell cycle arrest or apoptosis. MDM2 inhibits p53 activity by binding to the transactivation domain of p53 and by acting as a p53-specific E3 ubiquitin ligase. The disruption of the interaction between p53 and MDM2 with small molecular mass molecules has demonstrated encouraging single agent anti-tumor activity in preclinical in vitro and in vivo settings. While p53 wild-type status is necessary for response to antagonists of the p53-MDM2 protein-protein interaction (PPI), there is diversity in response to such therapeutic agents across p53 wild-type tumor models. As such, the ability to predict p53 wild-type tumor responsiveness to antagonists of the p53-MDM2 PPI is an unmet need that could significantly impact clinical development of modulators of the p53-MDM2 PPI. Here, we explored the effect of SAR405838, a selective p53-MDM2 antagonist, on a panel of 65 p53 wild-type cell lines derived from different tumors of origin. Over 80% of these cell lines showed some degree of sensitivity to SAR405838 when used as a single agent. Three broad response classes were observed: non-responders, responders involving apoptosis, and responders not involving apoptosis. A small number of tissue types were consistently enriched among responders (melanoma and leukemia) and non-responders (cervical and uterine tumors). By comparing pre-treatment gene expression profiling data with the single agent sensitivity to SAR405838, we identified a signature of 39 genes that clearly predicts non-response vs response. Within these 39 genes, CDKN2A was upregulated in non-responders, and MDM2 was upregulated in responders. Gene set enrichment analysis and GO category enrichments were consistent with predicted sensitivity in melanoma and leukemia, and indicate that a gene expression signature of loss of p53 pathway function predicts lack of single agent activity of SAR405838. 3-fold cross-validation of this classifier showed an accuracy of 94%, and principle component analyses was used to down-select the signature to the smallest number of genes carrying the maximum information and derive the optimal cut-off for making prospective response predictions. These data indicate that the development of p53-MDM2 PPI modulators could be targeted to a subset of p53 wild-type cancer patients and eliminate more predicted non-responders than those harbouring somatic mutations in p53.

Citation Format: James Watters, Steve Rowley, Laurent Debussche. Integrated profiling of p53 wild-type cell lines identifies differentially responsive populations and a gene expression signature that predicts sensitivity to SAR405838, a potent and selective disruptor of the p53-MDM2 interaction. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3436. doi:10.1158/1538-7445.AM2013-3436