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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Aurora Kinase A / antagonists & inhibitors*
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Aurora Kinase A / metabolism*
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Carcinoma, Non-Small-Cell Lung / drug therapy*
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Carcinoma, Non-Small-Cell Lung / genetics
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Cell Line, Tumor
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Cell Survival
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DNA Helicases / genetics
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DNA Helicases / metabolism*
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Female
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Gene Expression Regulation, Neoplastic
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Genome-Wide Association Study
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High-Throughput Nucleotide Sequencing
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Humans
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / genetics
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Mice
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Mice, SCID
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Mutation
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Neoplasms, Experimental
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Piperazines / pharmacology*
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Protein Kinase Inhibitors / pharmacology
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RNA Interference
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RNA, Small Interfering
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Transcription Factors / genetics
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Transcription Factors / metabolism*
Substances
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Nuclear Proteins
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Piperazines
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Protein Kinase Inhibitors
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RNA, Small Interfering
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Transcription Factors
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tozasertib
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Aurora Kinase A
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SMARCA4 protein, human
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DNA Helicases