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A distinct p53 target gene set predicts for response to the selective p53–HDM2 inhibitor NVP-CGM097

Jeay, Sebastien and Gaulis, Swann and Ferretti, Stephane Raymond and Bitter, Hans and Ito, Moriko and Valat, Therese-Marie and Murakami, Masato and Ruetz, Stephan and Guthy, Daniel Alexander and Rynn, Caroline and Jensen, Michael Rugaard and Wiesmann, Marion and Kallen, Joerg and Furet, Pascal and Gessier, Francois and Holzer, Philipp and Masuya, Keiichi and Wuerthner, Jens and Halilovic, Ensar and Hofmann, Francesco and Sellers, William and Graus Porta, Diana (2015) A distinct p53 target gene set predicts for response to the selective p53–HDM2 inhibitor NVP-CGM097. eLife, 4. ISSN 2050-084X

Abstract

Biomarkers for patient selection are essential for the successful and rapid development of emerging targeted anti-cancer therapeutics. In this study, we report the discovery of a novel patient selection strategy for the p53–HDM2 inhibitor NVP-CGM097, currently under evaluation in clinical trials. By intersecting high-throughput cell line sensitivity data with genomic data, we have identified a gene expression signature consisting of 13 up-regulated genes that predicts for sensitivity to NVP-CGM097 in both cell lines and in patientderived xenograft models. Interestingly, these 13 genes are known p53 downstream target genes, suggesting that the identified gene signature reflects the presence of at least a partially activated p53 pathway in NVP-CGM097-sensitive tumors. Together, our findings provide evidence for the use of this newly identified predictive gene signature to refine the selection of patients with wild-type p53 tumors and increase the likelihood of response to treatment with p53–HDM2 inhibitors, such as NVP-CGM097.

Item Type: Article
Keywords: NVP-CGM097, predictive signature, p53, HDM2, patient selection
Date Deposited: 13 Oct 2015 13:11
Last Modified: 04 Jul 2016 23:45
URI: https://oak.novartis.com/id/eprint/24527

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