23 Citations (Scopus)

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.

Original languageEnglish (US)
Article number14098
JournalNature Communications
Volume8
DOIs
StatePublished - Jan 19 2017

Fingerprint

Aurora Kinase A
mutations
Non-Small Cell Lung Carcinoma
lungs
inhibitors
cancer
Cells
Mutation
sensitivity
cells
proteins
spindles
biomarkers
apoptosis
death
genes
Centrosome
Spindle Apparatus
mice
depletion

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

SMARCA4-inactivating mutations increase sensitivity to Aurora kinase A inhibitor VX-680 in non-small cell lung cancers. / Tagal, Vural; Wei, Shuguang; Zhang, Wei; Brekken, Rolf A.; Posner, Bruce A.; Peyton, Michael; Girard, Luc; Hwang, Taehyun; Wheeler, David A.; Minna, John D.; White, Michael A.; Gazdar, Adi F.; Roth, Michael G.

In: Nature Communications, Vol. 8, 14098, 19.01.2017.

Research output: Contribution to journalArticle

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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.",
author = "Vural Tagal and Shuguang Wei and Wei Zhang and Brekken, {Rolf A.} and Posner, {Bruce A.} and Michael Peyton and Luc Girard and Taehyun Hwang and Wheeler, {David A.} and Minna, {John D.} and White, {Michael A.} and Gazdar, {Adi F.} and Roth, {Michael G.}",
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AU - Tagal, Vural

AU - Wei, Shuguang

AU - Zhang, Wei

AU - Brekken, Rolf A.

AU - Posner, Bruce A.

AU - Peyton, Michael

AU - Girard, Luc

AU - Hwang, Taehyun

AU - Wheeler, David A.

AU - Minna, John D.

AU - White, Michael A.

AU - Gazdar, Adi F.

AU - Roth, Michael G.

PY - 2017/1/19

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