Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Nature communications	8		2017 Jan 19	14098	Nat Commun

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	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
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	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	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	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