Loss of TBK1 Kinase Function Improves Disease Outcome in Pancreatic Cancer and Metabolic Syndrome
| dc.contributor.advisor | Castrillon, Diego H. | en |
| dc.contributor.committeeMember | Brekken, Rolf A. | en |
| dc.contributor.committeeMember | MacDonald, Raymond J. | en |
| dc.contributor.committeeMember | Scherer, Philipp | en |
| dc.creator | Cruz, Victoria Haley | en |
| dc.date.accessioned | 2020-09-01T21:04:29Z | |
| dc.date.available | 2020-09-01T21:04:29Z | |
| dc.date.created | 2018-08 | |
| dc.date.issued | 2018-07-30 | |
| dc.date.submitted | August 2018 | |
| dc.date.updated | 2020-09-01T21:04:29Z | |
| dc.description.abstract | Aberrant expression and activity of TANK binding kinase 1 (TBK1) has been observed in numerous diseases. Here I've identified novel functions for TBK1 in pancreatic ductal adenocarcinoma (PDA) and in metabolic syndrome that promote disease progression. Activating mutations in KRAS are present in 90% of human PDA cases; yet direct pharmacological inhibition of K-RAS remains a challenge, indicating a need for effective therapies. Higher levels of TBK1 mRNA, a critical downstream mediator of oncogenic K-RAS in lung cancer, correlate with poorer outcome in PDA patients. Given these observations, I hypothesized that TBK1 is also an effector of K-RAS in PDA. KRAS mutant PDA cell lines are selectively sensitive to small molecule inhibition of TBK1. In K-RAS-driven genetic mouse models of PDA, Tbk1 supports spontaneous pancreatic tumor growth as evidenced by smaller tumors and fewer metastases in Tbk1 mutant PDA mice relative to normal PDA mice. Additionally, Tbk1 mutant tumors are more epithelial; an observation consistent with the reduced migratory phenotype of Tbk1 mutant tumor cell lines and lack of detectable metastases in Tbk1 mutant PDA animals. Mechanistic studies indicate that TBK1 is central to Axl-driven EMT and is activated with RAS in response to Axl stimulation in PDA cell lines. The latter part of this thesis is focused on the contribution of TBK1 to mice with metabolic disorder. TBK1 is implicated in the regulation of metabolism through studies with amlexanox, an inhibitor of IκB kinase (IKK)-related kinases. Amlexanox induced weight loss, reduced fatty liver and insulin resistance in high fat diet (HFD) fed mice and has now progressed into clinical testing for the treatment and prevention of obesity and type 2 diabetes. However, since amlexanox is a dual IKKε/TBK1 inhibitor, the specific contribution of TBK1 is unclear. To distinguish metabolic functions unique to TBK1, I examined the metabolic profile of global Tbk1 mutant mice challenged with HFD and investigated potential mechanisms for the improved metabolic phenotype. I report that systemic loss of TBK1 kinase function has a protective effect on metabolic readouts in HFD-fed mice, which is mediated by loss of an inhibitory interaction between TBK1 and the insulin receptor. | en |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.oclc | 1192325712 | |
| dc.identifier.uri | https://hdl.handle.net/2152.5/8786 | |
| dc.language.iso | en | en |
| dc.subject | Carcinoma, Pancreatic Ductal | en |
| dc.subject | Metabolic Diseases | en |
| dc.subject | Pancreatic Neoplasms | en |
| dc.subject | Protein-Serine-Threonine Kinases | en |
| dc.subject | Proto-Oncogene Proteins | en |
| dc.subject | Receptor Protein-Tyrosine Kinases | en |
| dc.title | Loss of TBK1 Kinase Function Improves Disease Outcome in Pancreatic Cancer and Metabolic Syndrome | 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 |