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

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 G. Roth

doi:10.1038/ncomms14098

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

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 G. Roth

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71 Scopus citations

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 language	English (US)
Article number	14098
Journal	Nature communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms14098
State	Published - Jan 19 2017

ASJC Scopus subject areas

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

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Tagal, V., Wei, S., Zhang, W., Brekken, R. A., Posner, B. A., Peyton, M., Girard, L., Hwang, T., Wheeler, D. A., Minna, J. D., White, M. A., Gazdar, A. F., & Roth, M. G. (2017). SMARCA4-inactivating mutations increase sensitivity to Aurora kinase A inhibitor VX-680 in non-small cell lung cancers. Nature communications, 8, Article 14098. https://doi.org/10.1038/ncomms14098

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

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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doi = "10.1038/ncomms14098",

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AU - Wei, Shuguang

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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.

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N2 - 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.

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

Abstract

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