Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Mol Cell. 2024 Feb 15;84(4):776-790.e5. doi: 10.1016/j.molcel.2023.12.010. Epub 2024 Jan 10.
TANK-binding kinase 1 (TBK1) is a potential therapeutic target in multiple cancers, including clear cell renal cell carcinoma (ccRCC). However, targeting TBK1 in clinical practice is challenging. One approach to overcome this challenge would be to identify an upstream TBK1 regulator that could be targeted therapeutically in cancer specifically. In this study, we perform a kinome-wide small interfering RNA (siRNA) screen and identify doublecortin-like kinase 2 (DCLK2) as a TBK1 regulator in ccRCC. DCLK2 binds to and directly phosphorylates TBK1 on Ser172. Depletion of DCLK2 inhibits anchorage-independent colony growth and kidney tumorigenesis in orthotopic xenograft models. Conversely, overexpression of DCLK2, a short isoform that predominates in ccRCC, promotes ccRCC cell growth and tumorigenesis in vivo. Mechanistically, DCLK2 elicits its oncogenic signaling via TBK1 phosphorylation and activation. Taken together, these results suggest that DCLK2 is a TBK1 activator and potential therapeutic target for ccRCC.
TANK 结合激酶 1（TBK1）是多种癌症，包括透明细胞肾细胞癌（ccRCC）的潜在治疗靶点。然而，在临床实践中靶向 TBK1 具有挑战性。克服这一挑战的一种方法是鉴定一种上游 TBK1 调节剂，该调节剂可以在癌症中进行特异性的治疗性靶向。在这项研究中，我们进行了激酶组全范围的小干扰 RNA（siRNA）筛选，并鉴定出双皮质激酶 2（DCLK2）是 ccRCC 中的 TBK1 调节剂。DCLK2 与 TBK1 结合并在 Ser172 上直接磷酸化 TBK1。DCLK2 的耗竭抑制了 ccRCC 细胞在原位异种移植模型中的锚定非依赖性集落生长和肾肿瘤发生。相反，DCLK2 的过表达，一种在 ccRCC 中占优势的短亚型，促进了体内 ccRCC 细胞的生长和肿瘤发生。从机制上讲，DCLK2 通过 TBK1 的磷酸化和激活引发其致癌信号。总之，这些结果表明 DCLK2 是 TBK1 的激活剂，也是 ccRCC 的潜在治疗靶点。
