Ye Liu, Liu Beibei, Huang Jingling, Zhao Xiaolin, Wang Yuan, Xu Yungen, Wang Shuping
Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, PR China.
Life Sci. 2024 Jan 1;336:122294. doi: 10.1016/j.lfs.2023.122294. Epub 2023 Nov 23.
Doublecortin-like kinase 1 (DCLK1), a significant constituent of the protein kinase superfamily and the doublecortin family, has been recognized as a prooncogenic factor that exhibits a strong association with the malignant progression and clinical prognosis of various cancers. DCLK1 serves as a stem cell marker that governs tumorigenesis, tumor cell reprogramming, and epithelial-mesenchymal transition. Multiple studies have indicated the capable of DCLK1 in regulating the DNA damage response and facilitating DNA damage repair. Additionally, DCLK1 is involved in the regulation of the immune microenvironment and the promotion of tumor immune evasion. Recently, DCLK1 has emerged as a promising therapeutic target for a multitude of cancers. Several small-molecule inhibitors of DCLK1 have been identified. Nevertheless, the biological roles of DCLK1 are mainly ambiguous, particularly with the disparities between its α- and β-form transcripts in the malignant progression of cancers, which impedes the development of more precisely targeted drugs. This article focuses on tumor stem cells, tumor epithelial-mesenchymal transition, the DNA damage response, and the tumor microenvironment to provide a comprehensive overview of the association between DCLK1 and tumor malignant progression, address unsolved questions and current challenges, and project future directions for targeting DCLK1 for the diagnosis and treatment of cancers.
双皮质素样激酶1（DCLK1）是蛋白激酶超家族和双皮质素家族的重要组成部分，已被公认为一种促癌因子，与多种癌症的恶性进展和临床预后密切相关。DCLK1作为一种干细胞标志物，在肿瘤发生、肿瘤细胞重编程和上皮-间质转化中发挥作用。多项研究表明，DCLK1能够调节DNA损伤反应并促进DNA损伤修复。此外，DCLK1还参与免疫微环境的调节并促进肿瘤免疫逃逸。最近，DCLK1已成为多种癌症有前景的治疗靶点。几种DCLK1的小分子抑制剂已被鉴定出来。然而，DCLK1的生物学作用主要仍不明确，尤其是其α和β形式转录本在癌症恶性进展中的差异，这阻碍了更精准靶向药物的开发。本文聚焦于肿瘤干细胞、肿瘤上皮-间质转化、DNA损伤反应和肿瘤微环境，全面概述DCLK1与肿瘤恶性进展之间的关联，解决未解决的问题和当前面临的挑战，并展望靶向DCLK1用于癌症诊断和治疗的未来方向。
