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Synergistic interactions with PI3K inhibition that induce apoptosis

  1. Yaara Zwang
  2. Oliver Jonas
  3. Casandra Chen
  4. Mikael L Rinne
  5. John G Doench
  6. Federica Piccioni
  7. Li Tan
  8. Hai-Tsang Huang
  9. Jinhua Wang
  10. Young Jin Ham
  11. Joyce O'Connell
  12. Patrick Bhola
  13. Mihir Doshi
  14. Matthew Whitman
  15. Michael Cima
  16. Anthony Letai
  17. David E Root
  18. Robert S Langer
  19. Nathanael S Gray
  20. William C Hahn  Is a corresponding author
  1. Broad Institute of Massachusetts Institute of Technology and Harvard, United States
  2. Massachusetts Institute of Technology, United States
  3. Dana Farber Cancer Institute, United States
  4. Dana-Farber Cancer Institute, United States
Research Article
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Cite this article as: eLife 2017;6:e24523 doi: 10.7554/eLife.24523

Abstract

Activating mutations involving the PI3K pathway occur frequently in human cancers. However, PI3K inhibitors primarily induce cell cycle arrest, leaving a significant reservoir of tumor cells that may acquire or exhibit resistance. We searched for genes that are required for the survival of PI3K mutant cancer cells in the presence of PI3K inhibition by conducting a genome scale shRNA-based apoptosis screen in a PIK3CA mutant human breast cancer cell. We identified 5 genes (PIM2, ZAK, TACC1, ZFR, ZNF565) whose suppression induced cell death upon PI3K inhibition. We showed that small molecule inhibitors of the PIM2 and ZAK kinases synergize with PI3K inhibition. In addition, using a microscale implementable device to deliver either siRNAs or small molecule inhibitors in vivo, we showed that suppressing these 5 genes with PI3K inhibition induced tumor regression. These observations identify targets whose inhibition synergizes with PI3K inhibitors and nominate potential combination therapies involving PI3K inhibition.

Article and author information

Author details

  1. Yaara Zwang

    Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, United States
    Competing interests
    No competing interests declared.
  2. Oliver Jonas

    The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
  3. Casandra Chen

    Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, United States
    Competing interests
    No competing interests declared.
  4. Mikael L Rinne

    Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, United States
    Competing interests
    No competing interests declared.
  5. John G Doench

    Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, United States
    Competing interests
    No competing interests declared.
  6. Federica Piccioni

    Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, United States
    Competing interests
    No competing interests declared.
  7. Li Tan

    Department of Cancer Biology, Dana Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  8. Hai-Tsang Huang

    Department of Cancer Biology, Dana Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  9. Jinhua Wang

    Department of Cancer Biology, Dana Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  10. Young Jin Ham

    Department of Cancer Biology, Dana Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  11. Joyce O'Connell

    Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, United States
    Competing interests
    No competing interests declared.
  12. Patrick Bhola

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  13. Mihir Doshi

    Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, United States
    Competing interests
    No competing interests declared.
  14. Matthew Whitman

    The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
  15. Michael Cima

    The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
  16. Anthony Letai

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  17. David E Root

    Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, United States
    Competing interests
    No competing interests declared.
  18. Robert S Langer

    The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
  19. Nathanael S Gray

    Department of Cancer Biology, Dana Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5354-7403
  20. William C Hahn

    Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, United States
    For correspondence
    william_hahn@dfci.harvard.edu
    Competing interests
    William C Hahn, Consultant for Novartis.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2840-9791

Funding

Congressionally Directed Medical Research Programs (W81XWH-12-1-0115)

  • Yaara Zwang

National Institutes of Health (U01 CA176058)

  • William C Hahn

National Cancer Institute (R21-CA177391)

  • Oliver Jonas

National Institutes of Health (R01 CA130988)

  • William C Hahn

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animals were maintained under conditions approved by the Institutional Animal Care and Use Committee at the Dana-Farber Cancer Institute (IACUC protocol #04-101) and at the Massachusetts Institute of Technology (IACUC protocol #0412-038-15).

Reviewing Editor

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

Publication history

  1. Received: December 21, 2016
  2. Accepted: May 30, 2017
  3. Accepted Manuscript published: May 31, 2017 (version 1)
  4. Version of Record published: June 21, 2017 (version 2)

Copyright

© 2017, Zwang 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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