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
  • 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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