1. Cancer Biology
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KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer

  1. Elsa Beyer Krall
  2. Belinda Wang
  3. Diana M Munoz
  4. Nina Ilic
  5. Srivatsan Raghavan
  6. Matthew J Niederst
  7. Kristine Yu
  8. David A Ruddy
  9. Andrew J Aguirre
  10. Jong Wook Kim
  11. Amanda J Redig
  12. Justin F Gainor
  13. Juliet A Williams
  14. John M Asara
  15. John G Doench
  16. Pasi A Janne
  17. Alice T Shaw
  18. Robert E McDonald III
  19. Jeffrey A Engelman
  20. Frank Stegmeier
  21. Michael R Schlabach
  22. William C Hahn  Is a corresponding author
  1. KSQ Therapeutics, United States
  2. Dana-Farber Cancer Institute, United States
  3. Novartis Institute for Biomedical Research, United States
  4. Massachusetts General Hospital, United States
  5. Beth Israel Deaconess Medical Center, United States
  6. Broad Institute of Harvard and MIT, United States
Research Article
  • Cited 63
  • Views 6,091
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Cite this article as: eLife 2017;6:e18970 doi: 10.7554/eLife.18970

Abstract

Inhibitors that target the receptor tyrosine kinase (RTK)/Ras/mitogen-activated protein kinase (MAPK) pathway have led to clinical responses in lung and other cancers, but some patients fail to respond and in those that do resistance inevitably occurs1-4. To understand intrinsic and acquired resistance to inhibition of MAPK signaling, we performed CRISPR-Cas9 gene deletion screens in the setting of BRAF, MEK, EGFR, and ALK inhibition. Loss of KEAP1, a negative regulator of NFE2L2/NRF2, modulated the response to BRAF, MEK, EGFR, and ALK inhibition in BRAF-, NRAS-, KRAS-, EGFR-, and ALK-mutant lung cancer cells. Treatment with inhibitors targeting the RTK/MAPK pathway increased reactive oxygen species (ROS) in cells with intact KEAP1, and loss of KEAP1 abrogated this increase. In addition, loss of KEAP1 altered cell metabolism to allow cells to proliferate in the absence of MAPK signaling. These observations suggest that alterations in the KEAP1/NRF2 pathway may promote survival in the presence of multiple inhibitors targeting the RTK/Ras/MAPK pathway.

Article and author information

Author details

  1. Elsa Beyer Krall

    KSQ Therapeutics, Cambridge, United States
    Competing interests
    No competing interests declared.
  2. Belinda Wang

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  3. Diana M Munoz

    Oncology Disease Area, Novartis Institute for Biomedical Research, Cambridge, United States
    Competing interests
    No competing interests declared.
  4. Nina Ilic

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  5. Srivatsan Raghavan

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  6. Matthew J Niederst

    Oncology Disease Area, Novartis Institute for Biomedical Research, Cambridge, United States
    Competing interests
    No competing interests declared.
  7. Kristine Yu

    Oncology Disease Area, Novartis Institute for Biomedical Research, Cambridge, United States
    Competing interests
    No competing interests declared.
  8. David A Ruddy

    Oncology Disease Area, Novartis Institute for Biomedical Research, Cambridge, United States
    Competing interests
    No competing interests declared.
  9. Andrew J Aguirre

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  10. Jong Wook Kim

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  11. Amanda J Redig

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  12. Justin F Gainor

    Department of Medicine, Massachusetts General Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  13. Juliet A Williams

    Oncology Disease Area, Novartis Institute for Biomedical Research, Cambridge, United States
    Competing interests
    No competing interests declared.
  14. John M Asara

    Department of Medicine, Beth Israel Deaconess Medical Center, Boston, United States
    Competing interests
    No competing interests declared.
  15. John G Doench

    Broad Institute of Harvard and MIT, Cambridge, United States
    Competing interests
    No competing interests declared.
  16. Pasi A Janne

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  17. Alice T Shaw

    Department of Medicine, Massachusetts General Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  18. Robert E McDonald III

    Oncology Disease Area, Novartis Institute for Biomedical Research, Cambridge, United States
    Competing interests
    No competing interests declared.
  19. Jeffrey A Engelman

    Oncology Disease Area, Novartis Institute for Biomedical Research, Cambridge, United States
    Competing interests
    No competing interests declared.
  20. Frank Stegmeier

    KSQ Therapeutics, Cambridge, United States
    Competing interests
    No competing interests declared.
  21. Michael R Schlabach

    KSQ Therapeutics, Cambridge, United States
    Competing interests
    No competing interests declared.
  22. William C Hahn

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    For correspondence
    william_hahn@dfci.harvard.edu
    Competing interests
    William C Hahn, A consultant and receives research support from Novartis.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2840-9791

Funding

National Cancer Institute (R01 CA130998)

  • William C Hahn

Dana-Farber Cancer Institute Hale Center for Pancreatic Cancer

  • Andrew J Aguirre

Perry S. Levy Endowed Fellowship

  • Andrew J Aguirre

Harvard Catalyst and Harvard Clinical and Translational Science Center (UL1 TR001102)

  • Andrew J Aguirre

National Cancer Institute (U01 CA176058)

  • William C Hahn

National Cancer Institute (U01 CA199253)

  • William C Hahn

Hope Funds for Cancer Research (Postdoctoral Fellowship HFCR-11-03-03)

  • Elsa Beyer Krall

National Institutes of Health (Postdoctoral Fellowship F32 CA189306)

  • Elsa Beyer Krall

Susan G. Komen Foundation (Postdoctoral Fellowship PDF12230602)

  • Nina Ilic

Terri Brodeur Breast Cancer Foundation (Postdoctoral Fellowship)

  • Nina Ilic

Pancreatic Cancer Action Network (Samuel Stroum Fellowship)

  • Andrew J Aguirre

American Society of Clinical Oncology (Young Investigator Award)

  • Andrew J Aguirre

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

Ethics

Animal experimentation: Mice were maintained and handled in accordance with the Novartis Institutes for Biomedical Research (NIBR) Animal Care and Use Committee protocols and regulations.

Reviewing Editor

  1. Martin McMahon, University of Utah Medical Schoo, United States

Publication history

  1. Received: June 21, 2016
  2. Accepted: January 31, 2017
  3. Accepted Manuscript published: February 1, 2017 (version 1)
  4. Version of Record published: February 13, 2017 (version 2)
  5. Version of Record updated: October 31, 2017 (version 3)

Copyright

© 2017, Krall 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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Further reading

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    The abscission checkpoint regulates the ESCRT membrane fission machinery and thereby delays cytokinetic abscission to protect genomic integrity in response to residual mitotic errors. The checkpoint is maintained by Aurora B kinase, which phosphorylates multiple targets, including CHMP4C, a regulatory ESCRT-III subunit necessary for this checkpoint. We now report the discovery that cytoplasmic abscission checkpoint bodies (ACBs) containing phospho-Aurora B and tri-phospho-CHMP4C develop during an active checkpoint. ACBs are derived from mitotic interchromatin granules, transient mitotic structures whose components are housed in splicing-related nuclear speckles during interphase. ACB formation requires CHMP4C, and the ESCRT factor ALIX also contributes. ACB formation is conserved across cell types and under multiple circumstances that activate the checkpoint. Finally, ACBs retain a population of ALIX, and their presence correlates with delayed abscission and delayed recruitment of ALIX to the midbody where it would normally promote abscission. Thus, a cytoplasmic mechanism helps regulate midbody machinery to delay abscission.