{"id":{"repo_id":"utswmed","oai_identifier":"oai:utswmed-ir.tdl.org:2152.5/3570"},"canonical_url":"https://search.dev.ndltd.org/etd/utswmed/oai:utswmed-ir.tdl.org:2152.5/3570","repository":{"repo_id":"utswmed","name":"University of Texas Southwestern Medical Center","base_url":"https://utswmed-ir.tdl.org/server/oai/request"},"display":{"title":"SMARCA4/BRG1-Inactivating Mutations as Potential Predictive Markers for Aurora Kinase A-Targeted Therapy in NSCLCs","abstract":"SMARCA4 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.","abstract_html":"SMARCA4 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.","abstract_has_math":false,"creators":["Tagal, Vural"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["White, Michael A.","Roth, Michael G.","Minna, John D.","Cobb, Melanie H."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2016,"date_issued":"2016-09-01T19:14:29Z","date_published":"2016-09-01T19:14:29Z","updated_at":"2026-07-24T05:52:17Z","subjects":["Aurora Kinase A","Carcinoma, Non-Small-Cell Lung","DNA Helicases","Nuclear Proteins","Transcription Factors"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["957676360"],"render_values":[{"text":"957676360","href":null,"code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/2152.5/3570","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["White, Michael A.","Roth, Michael G.","Minna, John D.","Cobb, Melanie H."]},{"key":"dc:creator","label":"Author","values":["Tagal, Vural"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2016-09-01T19:14:29Z","2014-08","2014-05-28","August 2014","2016-09-01T19:07:03Z"]},{"key":"dc:type","label":"Dc Type","values":["Thesis","text"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Aurora Kinase A","Carcinoma, Non-Small-Cell Lung","DNA Helicases","Nuclear Proteins","Transcription Factors"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2152.5/3570","957676360"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["SMARCA4 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."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["SMARCA4/BRG1-Inactivating Mutations as Potential Predictive Markers for Aurora Kinase A-Targeted Therapy in NSCLCs"]}]}],"canonical_facts":{"dc:contributor":["White, Michael A.","Roth, Michael G.","Minna, John D.","Cobb, Melanie H."],"dc:creator":["Tagal, Vural"],"dc:date":["2016-09-01T19:14:29Z","2014-08","2014-05-28","August 2014","2016-09-01T19:07:03Z"],"dc:description":["SMARCA4 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."],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2152.5/3570","957676360"],"dc:language":["en"],"dc:subject":["Aurora Kinase A","Carcinoma, Non-Small-Cell Lung","DNA Helicases","Nuclear Proteins","Transcription Factors"],"dc:title":["SMARCA4/BRG1-Inactivating Mutations as Potential Predictive Markers for Aurora Kinase A-Targeted Therapy in NSCLCs"],"dc:type":["Thesis","text"]},"updated_at":"2026-07-24T05:52:17Z"}