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Nat Commun. 2017 Jan 19;8:14098. doi: 10.1038/ncomms14098.

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

Author information

1
Department of Biochemistry, UT Southwestern, Dallas, Texas 75390, USA.
2
Department of Pathology, UT Southwestern, Dallas, Texas 75390, USA.
3
Hamon Center for Therapeutic Oncology Research, UT Southwestern, Dallas, Texas 75390, USA.
4
Department of Pharmacology, UT Southwestern, Dallas, Texas 75390, USA.
5
Harold Simmons Comprehensive Cancer Center, UT Southwestern, Dallas, Texas 75390, USA.
6
Department of Clinical Sciences, UT Southwestern, Dallas, Texas 75390, USA.
7
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
8
Department of Medicine, UT Southwestern, Dallas, Texas 75390, USA.
9
Department of Cell Biology, UT Southwestern, Dallas, Texas 75390, USA.

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.

PMID:
28102363
PMCID:
PMC5253647
DOI:
10.1038/ncomms14098
[Indexed for MEDLINE]
Free PMC Article

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