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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers / metabolism*
  • Cell Line, Tumor
  • Fluorescence Resonance Energy Transfer
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Isoquinolines / pharmacology*
  • Neoplasms / drug therapy*
  • Oligonucleotide Array Sequence Analysis
  • Patient Selection*
  • Piperazines / pharmacology*
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Biomarkers
  • Isoquinolines
  • NVP-CGM097
  • Piperazines
  • Tumor Suppressor Protein p53
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2

Grants and funding

All research costs were covered by Novartis AG. No additional external funding was received for this study. The funder had no role in study design, data collection and interpretation, or the decision to submit the work for publication.