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 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.

Article and author information

Author details

  1. Sébastien Jeay

    Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland
    Competing interests
    Sébastien Jeay, Employee of Novartis Institutes for BioMedical Research.
  2. Swann Gaulis

    Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland
    Competing interests
    Swann Gaulis, Employee of Novartis Institutes for BioMedical Research.
  3. Stéphane Ferretti

    Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland
    Competing interests
    Stéphane Ferretti, Employee of Novartis Institutes for BioMedical Research.
  4. Hans Bitter

    Disease Area Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States
    Competing interests
    Hans Bitter, Employee of Novartis Institutes for BioMedical Research.
  5. Moriko Ito

    Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland
    Competing interests
    Moriko Ito, Employee of Novartis Institutes for BioMedical Research.
  6. Thérèse Valat

    Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland
    Competing interests
    Thérèse Valat, Employee of Novartis Institutes for BioMedical Research.
  7. Masato Murakami

    Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland
    Competing interests
    Masato Murakami, Employee of Novartis Institutes for BioMedical Research.
  8. Stephan Ruetz

    Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland
    Competing interests
    Stephan Ruetz, Employee of Novartis Institutes for BioMedical Research.
  9. Daniel A Guthy

    Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland
    Competing interests
    Daniel A Guthy, Employee of Novartis Institutes for BioMedical Research.
  10. Caroline Rynn

    Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, Basel, Switzerland
    Competing interests
    Caroline Rynn, Employee of Novartis Institutes for BioMedical Research.
  11. Michael R Jensen

    Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland
    Competing interests
    Michael R Jensen, Employee of Novartis Institutes for BioMedical Research.
  12. Marion Wiesmann

    Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland
    Competing interests
    Marion Wiesmann, Employee of Novartis Institutes for BioMedical Research.
  13. Joerg Kallen

    Center of Proteomic Chemistry, Novartis Institutes for BioMedical Research, Basel, Switzerland
    Competing interests
    Joerg Kallen, Employee of Novartis Institutes for BioMedical Research.
  14. Pascal Furet

    Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Basel, Switzerland
    Competing interests
    Pascal Furet, Employee of Novartis Institutes for BioMedical Research.
  15. François Gessier

    Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Basel, Switzerland
    Competing interests
    François Gessier, Employee of Novartis Institutes for BioMedical Research.
  16. Philipp Holzer

    Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Basel, Switzerland
    Competing interests
    Philipp Holzer, Employee of Novartis Institutes for BioMedical Research.
  17. Keiichi Masuya

    Peptidream Inc, Tokyo, Japan
    Competing interests
    Keiichi Masuya, was an employee of Novartis Institutes for BioMedical Research and is now an employee of Peptidream Inc. and has ownership interest (including patents) in Peptidream Inc.
  18. Jens Würthner

    Translational Clinical Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland
    Competing interests
    Jens Würthner, Employee of Novartis Institutes for BioMedical Research.
  19. Ensar Halilovic

    Translational Clinical Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States
    Competing interests
    Ensar Halilovic, Employee of Novartis Institutes for BioMedical Research.
  20. Francesco Hofmann

    Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland
    Competing interests
    Francesco Hofmann, Employee of Novartis Institutes for BioMedical Research.
  21. William R Sellers

    Disease Area Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States
    Competing interests
    William R Sellers, Employee of Novartis Institutes for BioMedical Research. Holds the position of VP/Global Head of Oncology in Novartis Institutes for BioMedical Research and has ownership interest (including patents) in Novartis Pharmaceuticals.
  22. Diana Graus Porta

    Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland
    For correspondence
    diana.graus_porta@novartis.com
    Competing interests
    Diana Graus Porta, Employee of Novartis Institutes for BioMedical Research.

Ethics

Animal experimentation: All animal studies were conducted in accordance to procedures covered by permit number 1975 issued by the Kantonales Veterinäramt Basel-Stadt and strictly adhered to the Eidgenössisches Tierschutzgesetz and the Eidgenössische Tierschutzverordnung. All animals were allowed to adapt for 4 days and housed in a pathogen-controlled environment (5 mice/Type III cage) with access to food and water ad libitum and were identified with transponders.

Copyright

© 2015, Jeay et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Sébastien Jeay
  2. Swann Gaulis
  3. Stéphane Ferretti
  4. Hans Bitter
  5. Moriko Ito
  6. Thérèse Valat
  7. Masato Murakami
  8. Stephan Ruetz
  9. Daniel A Guthy
  10. Caroline Rynn
  11. Michael R Jensen
  12. Marion Wiesmann
  13. Joerg Kallen
  14. Pascal Furet
  15. François Gessier
  16. Philipp Holzer
  17. Keiichi Masuya
  18. Jens Würthner
  19. Ensar Halilovic
  20. Francesco Hofmann
  21. William R Sellers
  22. Diana Graus Porta
(2015)
A distinct p53 target gene set predicts for response to the selective p53-HDM2 inhibitor NVP-CGM097
eLife 4:e06498.
https://doi.org/10.7554/eLife.06498

Share this article

https://doi.org/10.7554/eLife.06498

Further reading

    1. Computational and Systems Biology
    2. Cancer Biology
    Dmitriy Sonkin
    Short Report Updated

    A number of TP53-MDM2 inhibitors are currently under investigation as therapeutic agents in a variety of clinical trials in patients with TP53 wild type tumors. Not all wild type TP53 tumors are sensitive to such inhibitors. In an attempt to improve selection of patients with TP53 wild type tumors, an mRNA expression signature based on 13 TP53 transcriptional target genes was recently developed (Jeay et al. 2015). Careful reanalysis of TP53 status in the study validation data set of cancer cell lines considered to be TP53 wild type detected TP53 inactivating alterations in 23% of cell lines. The subsequent reanalysis of the remaining TP53 wild type cell lines clearly demonstrated that unfortunately the 13-gene signature cannot predict response to TP53-MDM2 inhibitor in TP53 wild type tumors.