Abstract A003: Kinome-wide siRNA screening identifies DCLK2 as a TBK1 activator and therapeutic target for ccRCC

Abstract

Abstract TBK1 has been identified as a potential therapeutic target in multiple cancers. However, it is challenging to target TBK1 in clinical practice due to lack of selectivity for TBK1 inhibitors and its role involved in innate immune signaling. To overcome this difficulty, one approach would be to identify a critical upstream regulator of TBK1 that can be targeted therapeutically, especially in clear cell Renal Cell Carcinoma (ccRCC) displaying hyper-activated TBK1 activity due to VHL loss. In this study, we perform a kinome-wide siRNA screening and identify Doublecortin like kinase 2 (DCLK2) as a novel TBK1 regulator in ccRCC. DCLK2 binds with TBK1 and directly phosphorylates TBK1 on Ser172. Depletion of DCLK2 inhibits anchorage independent colony growth of kidney cancer cells as well as kidney tumorigenesis in orthotopic xenograft models. DCLK2 gene product contains multiple isoforms. Among them, a short isoform called DCLK2203 expresses predominantly in ccRCC. Overexpression of DCLK2203 promotes ccRCC cell growth and tumorigenesis in vivo, which elicits its oncogenic signaling via activating TBK1 phosphorylation. Taken together, our work suggest that DCLK2 is a novel TBK1 activator and potential therapeutic target for ccRCC. Citation Format: Lianxin Hu, Qing Zhang. Kinome-wide siRNA screening identifies DCLK2 as a TBK1 activator and therapeutic target for ccRCC [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr A003.