Identification of DCLK2-TBK1 signaling axis as a potential therapeutic target in kidney cancer

鉴定 DCLK2-TBK1 信号轴作为肾癌的潜在治疗靶点

• 批准号: 10752584
• 负责人: Qing Zhang
• 金额: $ 48.57万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10752584
• 关键词: ARNT gene; Cancer Cell Growth; Cell Proliferation; Cells; Clear cell renal cell carcinoma; Clinical; Complex; Data; Development; Disease; Foundations; Genes; Growth Cones; HIF1A gene; Hypoxia Inducible Factor; IRF3 gene; Immune; Immune signaling; Impairment; In Vitro; Interferon Type I; Kidney; Malignant Epithelial Cell; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Molecular; Natural Immunity; Neoplasm Metastasis; Oncogenic; Optic Nerve Injuries; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Play; Predisposition; Production; Protein Dephosphorylation; Proteins; Publishing; Radiation therapy; Renal carcinoma; Reporting; Resistance; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Specialized Program of Research Excellence; Specificity; Specimen; TANK-binding kinase 1; Testing; Therapeutic; Therapeutic Intervention; Tumor Promotion; Tumor Suppressor Proteins; Ubiquitination; VHL gene; Work; Xenograft procedure; cancer therapy; chemotherapy; experimental study; factor A; in vivo; inhibitor; insight; kidney cell; neoplastic cell; new therapeutic target; novel; novel therapeutic intervention; overexpression; patient derived xenograft model; phosphoproteomics; preservation; programs; therapeutic target; transcription factor; tumor; tumor growth; tumor xenograft; tumorigenesis; ubiquitin-protein ligase; upstream kinase

Project Summary Clear cell renal cell carcinoma (ccRCC), which accounts for approximately 85% of all renal cancers, is resistant to a variety of cancer therapies and is highly lethal. von Hippel-Lindau (VHL) is the most important tumor suppressor in renal cancer, its loss leads to hypoxia inducible factor α (HIFα, including HIF1α and HIF2α) accumulation. Although HIF2α inhibitor has been developed as a potential therapeutic target in renal cancer, only a small propotion of patients will respond to HIF2α inhibitore treatment, suggesting the importance of identifying additional therapeutic vulnerabilities in VHL-deficient kidney cancer. Our recently published work demonstrated that VHL loss activates TANK Binding Kinase 1 (TBK1), which plays a critical role in tumor cell proliferation, tumor growth and spontaneous metastasis. Targeting TBK1 inhibits VHL-deficient cancer cell growth while leaving VHL restored cells unaffected. While TBK1 is involved in innate immune signaling and phosphorylates the transcription factor IRF3, we did not observe p-IRF3 (or type I interferon production) in VHL- deficient cancers suggesting alternate functions for TBK1 in ccRCC. Thus, TBK1 is a promising therapeutic target. However, currently available inhibitors lack specificity and may impair innate immunity. Identification of TBK1 regulators in ccRCC may lead to development of more specific inhibitors that preserve TBK1 function in other compartments (i.e. immune cells). Through a kinome-wide siRNA screen, we identified Doublecortin Like Kinase 2 (DCLK2) as a potential TBK1 activator. DCLK2 depletion by multiple siRNAs decreased TBK1 phosphorylation and protein levels. Conversely, overexpression of DCLK2 induced TBK1 phosphorylation both in vitro and in vivo. While DCLK2 was reported to promote growth cone reformation after optic nerve injury, a role for DCLK2 in cancer is unexplored. Our preliminary data show that DCLK2 depletion reduced ccRCC cell proliferation, colony formation and xenograft tumor growth. We hypothesize that the DCLK2-TBK1 regulatory node serves as a novel signaling axis in ccRCCs with VHL loss that could be exploited therapeutically. This is the first study to characterize the role of DCLK2 in cancer. In addition, TBK1 is the first known DCLK2 kinase substrate in cancer. In Specific Aim 1, we will characterize the functional significance of DCLK2 in kidney cancer. In Specific Aim 2, we will delineate the molecular mechanism by which DCLK2 contributes to kidney tumorigenesis. In Specific Aim 3, we will investigate the therapeutic potential of targeting DCLK2-TBK1 in kidney cancer ortothopic xenografts and patient derived xenografts (PDXs) available through UT Southwestern Kidney Cancer Specialized Program of Research Excellence (SPORE). Successful completion of these aims will provide mechanistic insight into a novel signaling pathway and set the foundation for therapeutic interventions targeting the DCLK2-TBK1 axis in ccRCC.

项目总结