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

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $446,286

## Abstract

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.

## Key facts

- **NIH application ID:** 10909301
- **Project number:** 5R01CA284591-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Qing Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $446,286
- **Award type:** 5
- **Project period:** 2023-09-01 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10909301

## Citation

> US National Institutes of Health, RePORTER application 10909301, Identification of DCLK2-TBK1 signaling axis as a potential therapeutic target in kidney cancer (5R01CA284591-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10909301. Licensed CC0.

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