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SMARCA4-inactivating mutations increase sensitivity to Aurora kinase A inhibitor VX-680 in non-small cell lung cancers

Author

Listed:
  • Vural Tagal

    (UT Southwestern)

  • Shuguang Wei

    (UT Southwestern)

  • Wei Zhang

    (UT Southwestern
    Hamon Center for Therapeutic Oncology Research, UT Southwestern)

  • Rolf A. Brekken

    (Hamon Center for Therapeutic Oncology Research, UT Southwestern
    UT Southwestern
    Harold Simmons Comprehensive Cancer Center, UT Southwestern)

  • Bruce A. Posner

    (UT Southwestern
    Harold Simmons Comprehensive Cancer Center, UT Southwestern)

  • Michael Peyton

    (Hamon Center for Therapeutic Oncology Research, UT Southwestern)

  • Luc Girard

    (Hamon Center for Therapeutic Oncology Research, UT Southwestern
    UT Southwestern)

  • TaeHyun Hwang

    (UT Southwestern)

  • David A. Wheeler

    (Baylor College of Medicine)

  • John D. Minna

    (Hamon Center for Therapeutic Oncology Research, UT Southwestern
    UT Southwestern
    Harold Simmons Comprehensive Cancer Center, UT Southwestern
    UT Southwestern)

  • Michael A. White

    (Harold Simmons Comprehensive Cancer Center, UT Southwestern
    UT Southwestern)

  • Adi F. Gazdar

    (UT Southwestern
    Hamon Center for Therapeutic Oncology Research, UT Southwestern
    Harold Simmons Comprehensive Cancer Center, UT Southwestern)

  • Michael G. Roth

    (UT Southwestern
    Harold Simmons Comprehensive Cancer Center, UT Southwestern)

Abstract

Mutations in the SMARCA4/BRG1 gene resulting in complete loss of its protein (BRG1) occur frequently in non-small cell lung cancer (NSCLC) cells. Currently, no single therapeutic agent has been identified as synthetically lethal with SMARCA4/BRG1 loss. We identify AURKA activity as essential in NSCLC cells lacking SMARCA4/BRG1. In these cells, RNAi-mediated depletion or chemical inhibition of AURKA induces apoptosis and cell death in vitro and in xenograft mouse models. Disc large homologue-associated protein 5 (HURP/DLGAP5), required for AURKA-dependent, centrosome-independent mitotic spindle assembly is essential for the survival and proliferation of SMARCA4/BRG1 mutant but not of SMARCA4/BRG1 wild-type cells. AURKA inhibitors may provide a therapeutic strategy for biomarker-driven clinical studies to treat the NSCLCs harbouring SMARCA4/BRG1-inactivating mutations.

Suggested Citation

  • Vural Tagal & Shuguang Wei & Wei Zhang & Rolf A. Brekken & Bruce A. Posner & Michael Peyton & Luc Girard & TaeHyun Hwang & David A. Wheeler & John D. Minna & Michael A. White & Adi F. Gazdar & Michael, 2017. "SMARCA4-inactivating mutations increase sensitivity to Aurora kinase A inhibitor VX-680 in non-small cell lung cancers," Nature Communications, Nature, vol. 8(1), pages 1-13, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14098
    DOI: 10.1038/ncomms14098
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