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1.
JCI Insight ; 52019 04 02.
Article in English | MEDLINE | ID: mdl-30938713

ABSTRACT

Pancreatic ductal adenocarcinoma (PDA) is characterized by an activating mutation in KRAS. Direct inhibition of KRAS through pharmacological means remains a challenge; however, targeting key KRAS effectors has therapeutic potential. We investigated the contribution of TANK-binding kinase 1 (TBK1), a critical downstream effector of mutant active KRAS, to PDA progression. We report that TBK1 supports the growth and metastasis of KRAS-mutant PDA by driving an epithelial plasticity program in tumor cells that enhances invasive and metastatic capacity. Further, we identify that the receptor tyrosine kinase Axl induces TBK1 activity in a Ras-RalB-dependent manner. These findings demonstrate that TBK1 is central to an Axl-driven epithelial-mesenchymal transition in KRAS-mutant PDA and suggest that interruption of the Axl-TBK1 signaling cascade above or below KRAS has potential therapeutic efficacy in this recalcitrant disease.


Subject(s)
Carcinoma, Pancreatic Ductal/metabolism , Pancreatic Neoplasms/metabolism , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , Receptor Protein-Tyrosine Kinases/metabolism , Animals , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/pathology , Cell Line, Tumor , Cyclin-Dependent Kinase Inhibitor p16/genetics , Epithelial-Mesenchymal Transition , Female , Gene Expression Regulation, Neoplastic , Genes, p16 , Humans , Lung/pathology , Mice, Inbred NOD , Mice, SCID , Pancreas/pathology , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Protein Serine-Threonine Kinases/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism , Signal Transduction , Wound Healing , ral GTP-Binding Proteins/metabolism , Axl Receptor Tyrosine Kinase
2.
Mol Metab ; 16: 139-149, 2018 10.
Article in English | MEDLINE | ID: mdl-29935921

ABSTRACT

OBJECTIVE: TANK Binding Kinase 1 (TBK1) has been implicated in the regulation of metabolism through studies with the drug amlexanox, an inhibitor of the 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 metabolic contribution of TBK1 is not clear. METHODS: To distinguish metabolic functions unique to TBK1, we examined the metabolic profile of global Tbk1 mutant mice challenged with an obesogenic diet and investigated potential mechanisms for the improved metabolic phenotype. RESULTS AND CONCLUSION: We report that systemic loss of TBK1 kinase function has an overall protective effect on metabolic readouts in mice on an obesogenic diet, which is mediated by loss of an inhibitory interaction between TBK1 and the insulin receptor.


Subject(s)
Metabolic Diseases/enzymology , Protein Serine-Threonine Kinases/deficiency , Aminopyridines/pharmacology , Animals , Body Weight , Diet, High-Fat , Disease Models, Animal , Fatty Liver/drug therapy , Fatty Liver/metabolism , I-kappa B Kinase/metabolism , Insulin/metabolism , Insulin Resistance , Male , Metabolic Diseases/genetics , Metabolic Diseases/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Obesity/metabolism , Phosphorylation , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Signal Transduction , Weight Loss
3.
J Cell Commun Signal ; 12(1): 83-90, 2018 Mar.
Article in English | MEDLINE | ID: mdl-29218456

ABSTRACT

TANK-binding kinase 1 (TBK1) is central to multiple biological processes that promote tumorigenesis including cell division, autophagy, innate immune response and AKT-pro survival signaling. TBK1 is well studied and most known for its function in innate immunity. However, the serine threonine protein kinase received significant attention as a synthetic lethal partner and effector of the major oncogene, RAS. This review summarizes newly identified cancer promoting functions of TBK1 and evaluates the therapeutic potential of targeting TBK1 in cancer.

4.
Cancer Res ; 78(1): 246-255, 2018 01 01.
Article in English | MEDLINE | ID: mdl-29180468

ABSTRACT

Activation of the receptor tyrosine kinase Axl is associated with poor outcomes in pancreatic cancer (PDAC), where it coordinately mediates immune evasion and drug resistance. Here, we demonstrate that the selective Axl kinase inhibitor BGB324 targets the tumor-immune interface to blunt the aggressive traits of PDAC cells in vitro and enhance gemcitibine efficacy in vivo Axl signaling stimulates the TBK1-NFκB pathway and innate immune suppression in the tumor microenvironment. In tumor cells, BGB324 treatment drove epithelial differentiation, expression of nucleoside transporters affecting gemcitabine response, and an immune stimulatory microenvironment. Our results establish a preclinical mechanistic rationale for the clinical development of Axl inhibitors to improve the treatment of PDAC patients.Significance: These results establish a preclinical mechanistic rationale for the clinical development of AXL inhibitors to improve the treatment of PDAC patients. Cancer Res; 78(1); 246-55. ©2017 AACR.


Subject(s)
Benzocycloheptenes/pharmacology , Carcinoma, Pancreatic Ductal/drug therapy , Pancreatic Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins/antagonists & inhibitors , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Triazoles/pharmacology , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Benzocycloheptenes/administration & dosage , Carcinoma, Pancreatic Ductal/immunology , Cell Line, Tumor , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Female , Humans , Male , Mice, Inbred C57BL , Mice, Transgenic , Molecular Targeted Therapy , Pancreatic Neoplasms/immunology , Triazoles/administration & dosage , Xenograft Model Antitumor Assays , Gemcitabine , Axl Receptor Tyrosine Kinase
5.
Cancer Res ; 76(4): 773-86, 2016 Feb 15.
Article in English | MEDLINE | ID: mdl-26676752

ABSTRACT

Aberrant signaling through cytokine receptors and their downstream signaling pathways is a major oncogenic mechanism underlying hematopoietic malignancies. To better understand how these pathways become pathologically activated and to potentially identify new drivers of hematopoietic cancers, we developed a high-throughput functional screening approach using ex vivo mutagenesis with the Sleeping Beauty transposon. We analyzed over 1,100 transposon-mutagenized pools of Ba/F3 cells, an IL3-dependent pro-B-cell line, which acquired cytokine independence and tumor-forming ability. Recurrent transposon insertions could be mapped to genes in the JAK/STAT and MAPK pathways, confirming the ability of this strategy to identify known oncogenic components of cytokine signaling pathways. In addition, recurrent insertions were identified in a large set of genes that have been found to be mutated in leukemia or associated with survival, but were not previously linked to the JAK/STAT or MAPK pathways nor shown to functionally contribute to leukemogenesis. Forced expression of these novel genes resulted in IL3-independent growth in vitro and tumorigenesis in vivo, validating this mutagenesis-based approach for identifying new genes that promote cytokine signaling and leukemogenesis. Therefore, our findings provide a broadly applicable approach for classifying functionally relevant genes in diverse malignancies and offer new insights into the impact of cytokine signaling on leukemia development.


Subject(s)
Carcinogenesis/genetics , Cell Transformation, Neoplastic/genetics , Leukemia/genetics , Animals , Humans , Leukemia/pathology , Mice , Mutagenesis , Signal Transduction
6.
Dis Model Mech ; 8(10): 1201-11, 2015 Oct 01.
Article in English | MEDLINE | ID: mdl-26438693

ABSTRACT

Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer-related deaths in the United States, and is projected to be second by 2025. It has the worst survival rate among all major cancers. Two pressing needs for extending life expectancy of affected individuals are the development of new approaches to identify improved therapeutics, addressed herein, and the identification of early markers. PDA advances through a complex series of intercellular and physiological interactions that drive cancer progression in response to organ stress, organ failure, malnutrition, and infiltrating immune and stromal cells. Candidate drugs identified in organ culture or cell-based screens must be validated in preclinical models such as KIC (p48(Cre);LSL-Kras(G12D);Cdkn2a(f/f)) mice, a genetically engineered model of PDA in which large aggressive tumors develop by 4 weeks of age. We report a rapid, systematic and robust in vivo screen for effective drug combinations to treat Kras-dependent PDA. Kras mutations occur early in tumor progression in over 90% of human PDA cases. Protein kinase and G-protein coupled receptor (GPCR) signaling activates Kras. Regulators of G-protein signaling (RGS) proteins are coincidence detectors that can be induced by multiple inputs to feedback-regulate GPCR signaling. We crossed Rgs16::GFP bacterial artificial chromosome (BAC) transgenic mice with KIC mice and show that the Rgs16::GFP transgene is a Kras(G12D)-dependent marker of all stages of PDA, and increases proportionally to tumor burden in KIC mice. RNA sequencing (RNA-Seq) analysis of cultured primary PDA cells reveals characteristics of embryonic progenitors of pancreatic ducts and endocrine cells, and extraordinarily high expression of the receptor tyrosine kinase Axl, an emerging cancer drug target. In proof-of-principle drug screens, we find that weanling KIC mice with PDA treated for 2 weeks with gemcitabine (with or without Abraxane) plus inhibitors of Axl signaling (warfarin and BGB324) have fewer tumor initiation sites and reduced tumor size compared with the standard-of-care treatment. Rgs16::GFP is therefore an in vivo reporter of PDA progression and sensitivity to new chemotherapeutic drug regimens such as Axl-targeted agents. This screening strategy can potentially be applied to identify improved therapeutics for other cancers.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Pancreatic Ductal/drug therapy , Drug Evaluation, Preclinical , Pancreatic Neoplasms/drug therapy , Albumin-Bound Paclitaxel/pharmacology , Albumin-Bound Paclitaxel/therapeutic use , Animals , Antineoplastic Agents/pharmacology , Biological Assay , Carcinogenesis/pathology , Carcinoma, Pancreatic Ductal/pathology , Cell Proliferation , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Deoxycytidine/therapeutic use , Genes, Reporter , Green Fluorescent Proteins/metabolism , Humans , Mice , Pancreatic Neoplasms/pathology , Proto-Oncogene Proteins/antagonists & inhibitors , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins p21(ras)/metabolism , RGS Proteins/metabolism , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Receptor Protein-Tyrosine Kinases/metabolism , Gemcitabine , Axl Receptor Tyrosine Kinase , Pancreatic Neoplasms
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