The CUL5 ubiquitin ligase complex mediates resistance to CDK9 and MCL1 inhibitors in lung cancer cells

Abstract

Overexpression of anti-apoptotic proteins MCL1 and Bcl-xL are frequently observed in many cancers. Inhibitors targeting MCL1 are in clinical development, however numerous cancer models are intrinsically resistant to this approach. To discover mechanisms underlying resistance to MCL1 inhibition, we performed multiple flow-cytometry based genome-wide CRISPR screens interrogating two drugs that directly (MCL1i) or indirectly (CDK9i) target MCL1. Remarkably, both screens identified three components (CUL5, RNF7 and UBE2F) of a cullin-RING ubiquitin ligase complex (CRL5) that resensitized cells to MCL1 inhibition. We find that levels of the BH3-only pro-apoptotic proteins Bim and Noxa are proteasomally regulated by the CRL5 complex. Accumulation of Noxa caused by depletion of CRL5 components was responsible for re-sensitization to CDK9 inhibitor, but not MCL1 inhibitor. Discovery of a novel role of CRL5 in apoptosis and resistance to multiple types of anti-cancer agents suggests the potential to improve combination treatments.

Data availability

Sequencing data is being deposited into SRA under accession code: SUB5033643

The following data sets were generated

Article and author information

Author details

  1. Shaheen Kabir

    Innovative Genomics Institute, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  2. Justin Cidado

    IMED Oncology, AstraZeneca, Waltham, United States
    Competing interests
    Justin Cidado, employed by AstraZeneca, from whom funded research support was received..
  3. Courtney Andersen

    IMED Oncology, AstraZeneca, Waltham, United States
    Competing interests
    Courtney Andersen, employed by AstraZeneca, from whom funded research support was received..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2064-2273
  4. Cortni Dick

    IMED Oncology, AstraZeneca, Waltham, United States
    Competing interests
    Cortni Dick, employed by AstraZeneca, from whom funded research support was received..
  5. Pei-Chun Lin

    Innovative Genomics Institute, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  6. Therese Mitros

    Innovative Genomics Institute, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  7. Hong Ma

    Innovative Genomics Institute, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  8. Seung Hyun Baik

    Innovative Genomics Institute, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  9. Matthew A Belmonte

    IMED Oncology, AstraZeneca, Waltham, United States
    Competing interests
    Matthew A Belmonte, employed by AstraZeneca, from whom funded research support was received..
  10. Lisa Drew

    IMED Oncology, AstraZeneca, Waltham, United States
    Competing interests
    Lisa Drew, employed by AstraZeneca, from whom funded research support was received..
  11. Jacob E Corn

    Innovative Genomics Institute, University of California, Berkeley, Berkeley, United States
    For correspondence
    jacob.corn@biol.ethz.ch
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7798-5309

Funding

AstraZeneca

  • Shaheen Kabir
  • Justin Cidado
  • Courtney Andersen
  • Cortni Dick
  • Pei-Chun Lin
  • Hong Ma
  • Matthew A Belmonte
  • Lisa Drew
  • Jacob E Corn

National Institutes of Health (DP2 HL141006)

  • Jacob E Corn

Li Ka Shing Foundation

  • Jacob E Corn

Heritage Medical Research Institute

  • Jacob E Corn

California Institute for Regenerative Medicine (DISC1-08776)

  • Shaheen Kabir
  • Seung Hyun Baik
  • Jacob E Corn

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

Reviewing Editor

  1. Michael R Green, Howard Hughes Medical Institute, University of Massachusetts Medical School, United States

Version history

  1. Received: December 15, 2018
  2. Accepted: July 5, 2019
  3. Accepted Manuscript published: July 11, 2019 (version 1)
  4. Version of Record published: August 20, 2019 (version 2)
  5. Version of Record updated: October 7, 2019 (version 3)

Copyright

© 2019, Kabir 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. Shaheen Kabir
  2. Justin Cidado
  3. Courtney Andersen
  4. Cortni Dick
  5. Pei-Chun Lin
  6. Therese Mitros
  7. Hong Ma
  8. Seung Hyun Baik
  9. Matthew A Belmonte
  10. Lisa Drew
  11. Jacob E Corn
(2019)
The CUL5 ubiquitin ligase complex mediates resistance to CDK9 and MCL1 inhibitors in lung cancer cells
eLife 8:e44288.
https://doi.org/10.7554/eLife.44288

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https://doi.org/10.7554/eLife.44288