1. Cancer Biology
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Combined ALK and MDM2 inhibition increases antitumor activity and overcomes resistance in human ALK mutant neuroblastoma cell lines and xenograft models

  1. Hui Qin Wang
  2. Ensar Halilovic
  3. Xiaoyan Li
  4. Jinsheng Liang
  5. Yichen Cao
  6. Daniel P Rakiec
  7. David A Ruddy
  8. Sebastien Jeay
  9. Jens U Wuerthner
  10. Noelito Timple
  11. Shailaja Kasibhatla
  12. Nanxin Li
  13. Juliet A Williams
  14. William R Sellers
  15. Alan Huang
  16. Fang Li  Is a corresponding author
  1. Novartis Institutes for BioMedical Research, United States
  2. Novartis Institutes for BioMedical Research, Switzerland
  3. Genomics Institute of the Novartis Research Foundation, United States
Research Article
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Cite this article as: eLife 2017;6:e17137 doi: 10.7554/eLife.17137

Abstract

The efficacy of ALK inhibitors in patients with ALK-mutant neuroblastoma is limited, highlighting the need to improve their effectiveness in these patients. To this end we sought to develop a combination strategy to enhance the antitumor activity of ALK inhibitor monotherapy in human neuroblastoma cell lines and xenograft models expressing activated ALK. Herein, we report that combined inhibition of ALK and MDM2 induced a complementary set of anti-proliferative and pro-apoptotic proteins. Consequently, this combination treatment synergistically inhibited proliferation of TP53 wild-type neuroblastoma cells harboring ALK amplification or mutations in vitro, and resulted in complete and durable responses in neuroblastoma xenografts derived from these cells. We further demonstrate that concurrent inhibition of MDM2 and ALK was able to overcome ceritinib resistance conferred by MYCN upregulation in vitro and in vivo. Together, combined inhibition of ALK and MDM2 may provide an effective treatment for TP53 wild-type neuroblastoma with ALK aberrations.

Article and author information

Author details

  1. Hui Qin Wang

    Disease Area Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Ensar Halilovic

    Disease Area Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Xiaoyan Li

    Disease Area Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jinsheng Liang

    Disease Area Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Yichen Cao

    Disease Area Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Daniel P Rakiec

    Disease Area Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. David A Ruddy

    Disease Area Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Sebastien Jeay

    Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  9. Jens U Wuerthner

    Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  10. Noelito Timple

    Genomics Institute of the Novartis Research Foundation, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Shailaja Kasibhatla

    Genomics Institute of the Novartis Research Foundation, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Nanxin Li

    Genomics Institute of the Novartis Research Foundation, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Juliet A Williams

    Disease Area Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. William R Sellers

    Disease Area Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Alan Huang

    Disease Area Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Fang Li

    Disease Area Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States
    For correspondence
    fli@tangotx.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0497-4200

Funding

Novartis

  • Fang Li

The research was funded by Novartis, Inc., where all authors were employees at the time the study was conducted. The authors declare no other competing financial interests.

Ethics

Animal experimentation: All in vivo studies were reviewed and approved by the Novartis Institutes of Biomedical Research Institutional Animal Care and Use Committee (IACUC) in accordance with applicable local, state, and federal regulations.If needed, a letter from the IACUC Chair can be provided to confirm that all in vivo studies were reviewed and approved by the Novartis IACUC. Below is the contact of the Novartis IACUC Chair.CeCe Brotchie-Fine, MA, CPIAManager, Animal Welfare ComplianceIACUC Chair & Animal Welfare OfficerT +1 617 871 5064M+1 617 834 4784Email: Candice.brotchie-fine@novartis.comNovartis Institutes for BioMedical Research, Inc.700 Main Street, 460 ACambridge, MA 02139 USA

Reviewing Editor

  1. Chi Van Dang, University of Pennsylvania, United States

Publication history

  1. Received: April 23, 2016
  2. Accepted: April 18, 2017
  3. Accepted Manuscript published: April 20, 2017 (version 1)
  4. Version of Record published: May 17, 2017 (version 2)

Copyright

© 2017, Wang 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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