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.
authors.affiliation: Department of Biochemistry, UT Southwestern, Dallas, Texas 75390, USA.
authors.forename: Vural
authors.initials: V
authors.lastname: Tagal
authors.affiliation: Department of Biochemistry, UT Southwestern, Dallas, Texas 75390, USA.
authors.forename: Shuguang
authors.initials: S
authors.lastname: Wei
authors.affiliation: Department of Pathology, UT Southwestern, Dallas, Texas 75390, USA.|Hamon Center for Therapeutic Oncology Research, UT Southwestern, Dallas, Texas 75390, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Hamon Center for Therapeutic Oncology Research, UT Southwestern, Dallas, Texas 75390, USA.|Department of Pharmacology, UT Southwestern, Dallas, Texas 75390, USA.|Harold Simmons Comprehensive Cancer Center, UT Southwestern, Dallas, Texas 75390, USA.
authors.forename: Rolf A
authors.identifier: 0000-0003-2704-2377
authors.initials: RA
authors.lastname: Brekken
authors.affiliation: Department of Biochemistry, UT Southwestern, Dallas, Texas 75390, USA.|Harold Simmons Comprehensive Cancer Center, UT Southwestern, Dallas, Texas 75390, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Posner
authors.affiliation: Hamon Center for Therapeutic Oncology Research, UT Southwestern, Dallas, Texas 75390, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Peyton
authors.affiliation: Hamon Center for Therapeutic Oncology Research, UT Southwestern, Dallas, Texas 75390, USA.|Department of Pharmacology, UT Southwestern, Dallas, Texas 75390, USA.
authors.forename: Luc
authors.initials: L
authors.lastname: Girard
authors.affiliation: Department of Clinical Sciences, UT Southwestern, Dallas, Texas 75390, USA.
authors.forename: TaeHyun
authors.initials: T
authors.lastname: Hwang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Wheeler
authors.affiliation: Hamon Center for Therapeutic Oncology Research, UT Southwestern, Dallas, Texas 75390, USA.|Department of Pharmacology, UT Southwestern, Dallas, Texas 75390, USA.|Harold Simmons Comprehensive Cancer Center, UT Southwestern, Dallas, Texas 75390, USA.|Department of Medicine, UT Southwestern, Dallas, Texas 75390, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.affiliation: Harold Simmons Comprehensive Cancer Center, UT Southwestern, Dallas, Texas 75390, USA.|Department of Cell Biology, UT Southwestern, Dallas, Texas 75390, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: White
authors.affiliation: Department of Pathology, UT Southwestern, Dallas, Texas 75390, USA.|Hamon Center for Therapeutic Oncology Research, UT Southwestern, Dallas, Texas 75390, USA.|Harold Simmons Comprehensive Cancer Center, UT Southwestern, Dallas, Texas 75390, USA.
authors.forename: Adi F
authors.initials: AF
authors.lastname: Gazdar
authors.affiliation: Department of Biochemistry, UT Southwestern, Dallas, Texas 75390, USA.|Harold Simmons Comprehensive Cancer Center, UT Southwestern, Dallas, Texas 75390, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Roth
mesh_terms: D000818:Animals; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D009374:Neoplasms, Experimental; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D064096:Aurora Kinase A; D004265:DNA Helicases; D009687:Nuclear Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D014157:Transcription Factors; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines; C084108:SMARCA4 protein, human