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SMARCA4 loss is synthetic lethal with CDK4/6 inhibition in non-small cell lung cancer

Author

Listed:
  • Yibo Xue

    (McGill University
    McGill University)

  • Brian Meehan

    (Montreal Children’s Hospital)

  • Zheng Fu

    (McGill University
    McGill University)

  • Xue Qing D. Wang

    (McGill University)

  • Pierre Olivier Fiset

    (McGill University Health Centre)

  • Ralf Rieker

    (University Hospital)

  • Cameron Levins

    (McGill University)

  • Tim Kong

    (McGill University
    McGill University)

  • Xianbing Zhu

    (McGill University
    McGill University)

  • Geneviève Morin

    (McGill University
    McGill University)

  • Lashanda Skerritt

    (McGill University
    McGill University)

  • Esther Herpel

    (Heidelberg University Hospital)

  • Sriram Venneti

    (University of Michigan Medical School)

  • Daniel Martinez

    (Children’s Hospital of Philadelphia Research Institute)

  • Alexander R. Judkins

    (Keck School of Medicine of University of Southern California)

  • Sungmi Jung

    (McGill University Health Centre)

  • Sophie Camilleri-Broet

    (McGill University Health Centre)

  • Anne V. Gonzalez

    (McGill University Health Centre)

  • Marie-Christine Guiot

    (McGill University Health Centre)

  • William W. Lockwood

    (British Columbia Cancer Agency
    University of British Columbia
    University of British Columbia)

  • Jonathan D. Spicer

    (McGill University Health Center)

  • Abbas Agaimy

    (University Hospital)

  • William A. Pastor

    (McGill University
    McGill University)

  • Josée Dostie

    (McGill University)

  • Janusz Rak

    (Montreal Children’s Hospital)

  • William D. Foulkes

    (McGill University
    McGill University
    Research Institute of the McGill University Health Centre, McGill University)

  • Sidong Huang

    (McGill University
    McGill University)

Abstract

Tumor suppressor SMARCA4 (BRG1), a key SWI/SNF chromatin remodeling gene, is frequently inactivated in cancers and is not directly druggable. We recently uncovered that SMARCA4 loss in an ovarian cancer subtype causes cyclin D1 deficiency leading to susceptibility to CDK4/6 inhibition. Here, we show that this vulnerability is conserved in non-small cell lung cancer (NSCLC), where SMARCA4 loss also results in reduced cyclin D1 expression and selective sensitivity to CDK4/6 inhibitors. In addition, SMARCA2, another SWI/SNF subunit lost in a subset of NSCLCs, also regulates cyclin D1 and drug response when SMARCA4 is absent. Mechanistically, SMARCA4/2 loss reduces cyclin D1 expression by a combination of restricting CCND1 chromatin accessibility and suppressing c-Jun, a transcription activator of CCND1. Furthermore, SMARCA4 loss is synthetic lethal with CDK4/6 inhibition both in vitro and in vivo, suggesting that FDA-approved CDK4/6 inhibitors could be effective to treat this significant subgroup of NSCLCs.

Suggested Citation

  • Yibo Xue & Brian Meehan & Zheng Fu & Xue Qing D. Wang & Pierre Olivier Fiset & Ralf Rieker & Cameron Levins & Tim Kong & Xianbing Zhu & Geneviève Morin & Lashanda Skerritt & Esther Herpel & Sriram Ven, 2019. "SMARCA4 loss is synthetic lethal with CDK4/6 inhibition in non-small cell lung cancer," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08380-1
    DOI: 10.1038/s41467-019-08380-1
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