2. Academic Validation
  3. A distinct p53 target gene set predicts for response to the selective p53-HDM2 inhibitor NVP-CGM097

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

  • Elife. 2015 May 12:4:e06498. doi: 10.7554/eLife.06498.
Sébastien Jeay 1,  Swann Gaulis 1,  Stéphane Ferretti 1,  Hans Bitter 2,  Moriko Ito 1,  Thérèse Valat 1,  Masato Murakami 1,  Stephan Ruetz 1,  Daniel A Guthy 1,  Caroline Rynn 3,  Michael R Jensen 1,  Marion Wiesmann 1,  Joerg Kallen 4,  Pascal Furet 5,  François Gessier 5,  Philipp Holzer 5,  Keiichi Masuya 5,  Jens Würthner 6,  Ensar Halilovic 7,  Francesco Hofmann 1,  William R Sellers 2,  Diana Graus Porta 1
Affiliations

Affiliations

  • 1 Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland.
  • 2 Disease Area Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States.
  • 3 Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, Basel, Switzerland.
  • 4 Center of Proteomic Chemistry, Novartis Institutes for BioMedical Research, Basel, Switzerland.
  • 5 Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Basel, Switzerland.
  • 6 Translational Clinical Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland.
  • 7 Translational Clinical Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States.
PMID: 25965177 DOI: 10.7554/eLife.06498
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 patient-derived tumor 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.

Keywords

HDM2; human; human biology; medicine; p53; predictive signature; translational oncology.

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