SMARCA4/BRG1-Inactivating Mutations as Potential Predictive Markers for Aurora Kinase A-Targeted Therapy in NSCLCs
| dc.contributor.advisor | White, Michael A. | en |
| dc.contributor.committeeMember | Roth, Michael G. | en |
| dc.contributor.committeeMember | Minna, John D. | en |
| dc.contributor.committeeMember | Cobb, Melanie H. | en |
| dc.creator | Tagal, Vural | en |
| dc.date.accessioned | 2016-09-01T19:14:29Z | |
| dc.date.available | 2016-09-01T19:14:29Z | |
| dc.date.created | 2014-08 | |
| dc.date.issued | 2014-05-28 | |
| dc.date.submitted | August 2014 | |
| dc.date.updated | 2016-09-01T19:07:03Z | |
| dc.description.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. | en |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.oclc | 957676360 | |
| dc.identifier.uri | https://hdl.handle.net/2152.5/3570 | |
| dc.language.iso | en | en |
| dc.subject | Aurora Kinase A | en |
| dc.subject | Carcinoma, Non-Small-Cell Lung | en |
| dc.subject | DNA Helicases | en |
| dc.subject | Nuclear Proteins | en |
| dc.subject | Transcription Factors | en |
| dc.title | SMARCA4/BRG1-Inactivating Mutations as Potential Predictive Markers for Aurora Kinase A-Targeted Therapy in NSCLCs | en |
| dc.type | Thesis | en |
| dc.type.material | text | en |
| thesis.degree.department | Graduate School of Biomedical Sciences | en |
| thesis.degree.discipline | Cancer Biology | en |
| thesis.degree.grantor | UT Southwestern Medical Center | en |
| thesis.degree.level | Doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |