Doublecortin-like kinase 1 is a therapeutic target in squamous cell carcinoma
Doublecortin-like kinase 1 is a therapeutic target in squamous cell carcinoma
Abstract Doublecortin like kinase 1 (DCLK1) plays a crucial role in several cancers including colon and pancreatic adenocarcinomas. However, its role in squamous cell carcinoma (SCC) remains unknown. To this end, we examined DCLK1 expression in head and neck squamous cell carcinoma (HNSCC) and anal squamous cell carcinoma (ASCC). We found that DCLK1 is elevated in patient SCC tissue, which correlated with cancer progression and poorer overall survival. Furthermore, DCLK1 expression is significantly elevated in HPV negative cancer tissues, which are typically aggressive with poor responses to radiation therapy. To understand the role of DCLK1 in tumorigenesis, we used specific shRNA to suppress DCLK1 expression. This significantly reduced tumor growth, spheroid formation, and migration of HNSCC cancer cells. To further the translational relevance of our studies, we sought to identify a selective DCLK1 inhibitor. Current attempts to target DCLK1 using pharmacologic approaches have relied on non-specific suppression of DCLK1 kinase activity. Here, we demonstrate that DiFiD [3,5-bis (2,4-difluorobenzylidene)-4-piperidone] binds to DCLK1 with high selectivity. Moreover, DiFiD mediated suppression of DCLK1 led to G2/M arrest and apoptosis and significantly suppressed tumor growth of HNSCC xenografts and ASCC patient derived xenografts, supporting that DCLK1 is critical for SCC growth.
Al-Rajabi Raed、Ottemann Brendan、Snyder Vusala、Sayed Afreen、Srinivasan Pugazhendhi、Choudhury Sonali、Ramamoorthy Prabhu、O?ˉNeil Maura、Gunewardena Sumedha、Umar Shahid、Padhye Subhash B.、Thomas Sufi Mary、New Jacob、Shadoin Melissa、Anant Shrikant、Weir Scott J.、Dandawate Prasad、Roy Badal C.、Ponnurangam Sivapriya、Kwatra Deep、Arnold Levi、Standing David、Tawfik Ossama、Subramaniam Dharmalingam、Ashcraft John
Department of Internal Medicine, University of Kansas Medical CenterDepartment of Otolaryngology, University of Kansas Medical CenterDepartment of Otolaryngology, University of Kansas Medical CenterDepartment of Cancer Biology, University of Kansas Medical CenterDepartment of Cancer Biology, University of Kansas Medical CenterDepartment of Cancer Biology, University of Kansas Medical CenterDepartment of Cancer Biology, University of Kansas Medical CenterDepartment of Pathology and Laboratory Medicine, University of Kansas Medical CenterDepartment of Molecular and Integrative Physiology, University of Kansas Medical CenterDepartment of General Surgery, University of Kansas Medical CenterInterdisciplinary Science and Technology Research Academy, Abeda Inamdar Senior CollegeDepartment of Cancer Biology, University of Kansas Medical Center||Department of Otolaryngology, University of Kansas Medical Center||Department of Anatomy and Cell Biology, University of Kansas Medical CenterDepartment of Otolaryngology, University of Kansas Medical Center||Department of Anatomy and Cell Biology, University of Kansas Medical CenterDepartment of Otolaryngology, University of Kansas Medical CenterDepartment of Cancer Biology, University of Kansas Medical CenterDepartment of Cancer Biology, University of Kansas Medical Center||Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center||Institute for Advancing Medical Innovation, University of Kansas Medical Center, Kansas CityDepartment of Cancer Biology, University of Kansas Medical CenterDepartment of General Surgery, University of Kansas Medical CenterDepartment of Cancer Biology, University of Kansas Medical CenterDepartment of Cancer Biology, University of Kansas Medical CenterDepartment of Cancer Biology, University of Kansas Medical CenterDepartment of Cancer Biology, University of Kansas Medical CenterDepartment of Pathology, Saint Luke?ˉs Health System, Kansas City, Missouri and MAWD Pathology GroupDepartment of Cancer Biology, University of Kansas Medical CenterDepartment of General Surgery, University of Kansas Medical Center
肿瘤学基础医学分子生物学
Al-Rajabi Raed,Ottemann Brendan,Snyder Vusala,Sayed Afreen,Srinivasan Pugazhendhi,Choudhury Sonali,Ramamoorthy Prabhu,O?ˉNeil Maura,Gunewardena Sumedha,Umar Shahid,Padhye Subhash B.,Thomas Sufi Mary,New Jacob,Shadoin Melissa,Anant Shrikant,Weir Scott J.,Dandawate Prasad,Roy Badal C.,Ponnurangam Sivapriya,Kwatra Deep,Arnold Levi,Standing David,Tawfik Ossama,Subramaniam Dharmalingam,Ashcraft John.Doublecortin-like kinase 1 is a therapeutic target in squamous cell carcinoma[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/2022.05.26.493670.点此复制
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