SMARCA4/BRG1-Inactivating Mutations as Potential Predictive Markers for Aurora Kinase A-Targeted Therapy in NSCLCs

dc.contributor.advisorWhite, Michael A.en
dc.contributor.committeeMemberRoth, Michael G.en
dc.contributor.committeeMemberMinna, John D.en
dc.contributor.committeeMemberCobb, Melanie H.en
dc.creatorTagal, Vuralen 2014
dc.description.abstractSMARCA4 encodes a catalytic subunit of the SWI/SNF chromatin remodeling complex, BRG1. Frequent occurrence of SMARCA4/BRG1-inactivating mutations and their mutually exclusive nature from EGFR and ALK lesions create one of the largest subsets of Non-Small Cell Lung Cancers (NSCLCs). Since these mutations have been identified as bona fide tumor suppressors, efforts have focused on understanding the pathology of cancer caused by SMARCA4/BRG1 aberrations. However, no therapeutic agent has been identified as synthetically lethal with SMARCA4/BRG1 loss. Utilizing genome-wide high-throughput small interfering RNA (siRNA)-based screening, we show here that Aurora kinase A (AURKA) activity is essential in NSCLCs carrying SMARCA4/BRG1-inactivating mutations. RNAi-mediated depletion or chemical inhibition of AURKA induces apoptosis and diminish cellular viability in SMARCA4/BRG1-mutant NSCLC cells in vitro and in mouse models. The relation between SMARCA4/BRG1 inactivation and increased requirement for AURKA appears to be due to the impairment of functional centrosomes. Thus, AURKA-centered, centrosome-independent, mitotic spindle assembly machinery becomes solely responsible for mitotic spindle formation and proper chromosome segregation during mitosis. DLG7, the only known protein specific to this centrosome-independent mitotic spindle assembly, is required for the survival and proliferation of cells with inactivated SMARCA4/BRG1. Depletion of DLG7 causes no effect in SMARCA4/BRG1-proficient cells, but significant decrease in cell viability occurs in SMARCA/BRG1-deficient NCI-H1819 cells and this cytotoxic effect can be rescued with the restoration of wild-type SMARCA4/BRG1 expression. Altogether, our findings identify AURKA inhibition with VX-680 as a candidate therapeutic strategy for biomarker-driven clinical studies to treat the NSCLCs harboring SMARCA4/BRG1 inactivation mutations, which account for approximately 35% of all NSCLC cases. Furthermore, these observations suggest a previously unrecognized concept of redundancy for mitotic spindle assembly machinery that has a potential use for cancer therapeutics.en
dc.subjectAurora Kinase Aen
dc.subjectCarcinoma, Non-Small-Cell Lungen
dc.subjectDNA Helicasesen
dc.subjectNuclear Proteinsen
dc.subjectTranscription Factorsen
dc.titleSMARCA4/BRG1-Inactivating Mutations as Potential Predictive Markers for Aurora Kinase A-Targeted Therapy in NSCLCsen
dc.type.materialtexten School of Biomedical Sciencesen Biologyen Southwestern Medical Centeren of Philosophyen


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