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Ref Type Journal Article
PMID (28102363)
Authors Tagal V, Wei S, Zhang W, Brekken RA, Posner BA, Peyton M, Girard L, Hwang T, Wheeler DA, Minna JD, White MA, Gazdar AF, Roth MG
Title SMARCA4-inactivating mutations increase sensitivity to Aurora kinase A inhibitor VX-680 in non-small cell lung cancers.
Journal Nature communications
Vol 8
Issue
Date 2017 Jan 19
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
SMARCA4 inact mut lung non-small cell carcinoma sensitive MK-5108 Preclinical - Cell culture Actionable In a preclinical study, a non-small cell lung cancer cell line harboring an inactivating mutation in SMARCA4 demonstrated sensitivity to MK-5108 (VX-689) in culture (PMID: 28102363). 28102363
SMARCA4 inact mut lung non-small cell carcinoma sensitive Danusertib Preclinical - Cell culture Actionable In a preclinical study, a non-small cell lung cancer cell line harboring an inactivating mutation in SMARCA4 demonstrated sensitivity to Danusertib (PHA-739358) in culture (PMID: 28102363). 28102363
SMARCA4 inact mut lung non-small cell carcinoma sensitive Tozasertib Preclinical - Cell line xenograft Actionable In a preclinical study, non-small cell lung cancer cell lines harboring SMARCA4 inactivating mutations demonstrated sensitivity to Tozasertib (VX-680) in culture and in xenograft models (PMID: 28102363). 28102363
SMARCA4 inact mut lung non-small cell carcinoma sensitive ENMD-2076 Preclinical - Cell culture Actionable In a preclinical study, a non-small cell lung cancer cell line harboring an inactivating mutation in SMARCA4 demonstrated sensitivity to ENMD-2076 in culture (PMID: 28102363). 28102363
SMARCA4 inact mut lung non-small cell carcinoma sensitive Alisertib Preclinical - Cell culture Actionable In a preclinical study, a non-small cell lung cancer cell line harboring an inactivating mutation in SMARCA4 demonstrated sensitivity to Alisertib (MLN8237) in culture (PMID: 28102363). 28102363