Context-Selective Support of the AKT/mTOR Regulatory Axis by Tank-Binding Kinase 1 (TBK1)
| dc.contributor.advisor | Brugarolas, James B. | en |
| dc.contributor.committeeMember | Cobb, Melanie H. | en |
| dc.contributor.committeeMember | Brekken, Rolf A. | en |
| dc.contributor.committeeMember | White, Michael A. | en |
| dc.creator | Cooper, Jonathan Mark | en |
| dc.creator.orcid | 0000-0002-7468-2062 | |
| dc.date.accessioned | 2019-01-03T21:04:54Z | |
| dc.date.available | 2019-01-03T21:04:54Z | |
| dc.date.created | 2016-12 | |
| dc.date.issued | 2016-11-28 | |
| dc.date.submitted | December 2016 | |
| dc.date.updated | 2019-01-03T21:04:54Z | |
| dc.description.abstract | Oncogenic mutation of Ras or Ras effector signaling characterizes roughly thirty percent of all cancers. Persistent obstacles to the treatment of these diseases by direct Ras inhibition prompt alternative strategies aimed at leveraging signaling networks downstream of Ras. Tank-Binding Kinase 1 (TBK1) is downstream of the RalGEF/RalB arm of Ras effector signaling and supports Ras-driven oncogenic transformation via direct regulation of AKT. While TBK1 has been nominated as a therapeutic target, the field lacks knowledge of the mechanisms whereby TBK1 inhibitors mediate lethality and of the preferential context(s) for their application. We therefore leveraged toxicity profiles for TBK1 inhibitors in 100 NSCLC cell lines and identified robust correlation between TBK1 inhibitors and a cadre of mTOR direct and upstream regulatory network signaling inhibitors. This observation, along with orthogonal phosphoproteomics data, suggested an intersection exists between TBK1 and mTOR regulation and mechanistic target space. We identified that TBK1 is required for AKT/mTOR activation during the nutrient starved-to-fed state transition. Furthermore, we established that TBK1 physically intersects with the AKT/mTOR regulatory axis signaling at multiple nodes and can follow permissive and instructive mechanistic routes to regulate mTORC1 activation in response to nutrients. In parallel, we utilized a bioinformatics approach to identify that "Ras-mutant/mesenchymal" status serves as a molecular indicator of TBK1 inhibitor sensitivity in NSCLC. Concordantly, signaling through the AKT/mTOR regulatory axis was acutely attenuated by TBK1 inhibition in Ras-mutant/mesenchymal but remained unresponsive in Ras-mutant/epithelial NSCLC, indicating TBK1-resistant NSCLC may have uncoupled AKT/mTOR signaling from substantive TBK1 regulation. We furthermore demonstrated that TBK1 inhibition synergizes with Transforming Growth Factor-beta (TGF-beta)-mediated induction of the epithelial-to-mesenchymal transition (EMT) to reduce cancer cell viability. Together, these observations suggest that TBK1 supports pro-survival signaling downstream of Ras and EMT/TGF-beta signaling through the AKT/mTOR regulatory axis. Our findings, therefore, reveal novel mechanistic contributions of TBK1 in the regulation of AKT/mTOR signaling, and also nominate Ras-mutant/mesenchymal NSCLC as the preferential context for therapeutic interventions targeting TBK1. | en |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.oclc | 1080644318 | |
| dc.identifier.uri | https://hdl.handle.net/2152.5/6140 | |
| dc.language.iso | en | en |
| dc.subject | Carcinoma, Non-Small-Cell Lung | en |
| dc.subject | Lung Neoplasms | en |
| dc.subject | Mesoderm | en |
| dc.subject | Protein-Serine-Threonine Kinases | en |
| dc.subject | Proto-Oncogene Proteins c-akt | en |
| dc.subject | Small Molecule Libraries | en |
| dc.subject | TOR Serine-Threonine Kinases | en |
| dc.title | Context-Selective Support of the AKT/mTOR Regulatory Axis by Tank-Binding Kinase 1 (TBK1) | 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 |