Doublecortin-Like Kinase 1 (DCLK1) Is a Novel NOTCH Pathway Signaling Regulator in Head and Neck Squamous Cell Carcinoma

Abstract

Despite recent advancements, the 5 year survival of head and neck squamous cell carcinoma (HNSCC) hovers at 60%. DCLK1 has been shown to regulate epithelial-to-mesenchymal transition as well as serving as a cancer stem cell marker in colon, pancreatic and renal cancer. Although it was reported that DCLK1 is associated with poor prognosis in oropharyngeal cancers, very little is known about the molecular characterization of DCLK1 in HNSCC. In this study, we performed a comprehensive transcriptome-based computational analysis on hundreds of HNSCC patients from TCGA and GEO databases, and found that DCLK1 expression positively correlates with NOTCH signaling pathway activation. Since NOTCH signaling has a recognized role in HNSCC tumorigenesis, we next performed a series of in vitro experiments in a collection of HNSCC cell lines to investigate the role of DCLK1 in NOTCH pathway regulation. Our analyses revealed that DCLK1 inhibition, using either a pharmacological inhibitor or siRNA, resulted in substantially decreased proliferation, invasion, migration, and colony formation. Furthermore, these effects paralleled downregulation of active NOTCH1, and its downstream effectors, HEY1, HES1 and HES5, whereas overexpression of DCLK1 in normal keratinocytes, lead to an upregulation of NOTCH signaling associated with increased proliferation. Analysis of 233 primary and 40 recurrent HNSCC cancer biopsies revealed that high DCLK1 expression was associated with poor prognosis and showed a trend towards higher active NOTCH1 expression in tumors with elevated DCLK1. Our results demonstrate the novel role of DCLK1 as a regulator of NOTCH signaling network and suggest its potential as a therapeutic target in HNSCC.

A nanoengineered topical transmucosal cisplatin delivery system induces anti-tumor response in animal models and patients with oral cancer

“…The multimodality treatment approach for locally advanced OCSCC has evolved over the last few decades, contributing to improvements in functional and esthetic outcomes 54 . However, despite these important advances, therapeutic options remain limited, and complications associated with surgical cancer ablation, long-term effects of radiation, and dose-limiting side effects of systemic cisplatin administration, still have a significant impact on the quality of life in patients with OCSCC 54 .…”

Inhibition of DCLK1 with DCLK1-IN-1 Suppresses Renal Cell Carcinoma Invasion and Stemness and Promotes Cytotoxic T-Cell-Mediated Anti-Tumor Immunity

“…In the context of these previous studies, our current findings are novel in several ways. DCLK1 is best known for its role as a tuft cell and CSC marker in gastrointestinal (GI) cancers, but a mounting body of literature supports its role in promoting non-GI malignancies including breast, lung, head and neck, and others [30,[32][33][34][35][36]. The current study represents, to our knowledge, the first reported study of DCLK1-IN-1 in a non-GI cancer.…”

“…Indeed, our prior attempts to use both XMD8-92 and LRRK2-IN-1 in MTT assays with ACHN and CAKI-2 cells (data not shown) demonstrated no effect on viability or proliferation whatsoever, even at concentrations > 100 µM. In contrast, these compounds elicit potent effects against cell viability/proliferation in other cancer types [19,27,30]. Moreover, as further support for this possibility, an examination of gene expression data from the Cancer Cell Line Encyclopedia (CCLE) demonstrates significantly increased expression of MDR1/P-Glycoprotein in all three RCC cell lines (ACHN, 786-O, and CAKI-1 with FPKMs of 5.37, 10.70, and 3.95, respectively) used in this study compared with most lines used in prior DCLK1-IN-1 studies (Patu-8988T, Patu-8902, MKN1, and DLD1 with FPKMs of 0.009, 0.023, 0.046, and 10.4, respectively).…”

“…Previous inhibitors showed affinity for DCLK1 kinase, but their use in studying this target was hampered by their effect on other targets such as ERK5, LRRK2, and BRD4 bromodomain [17]. In particular, LRRK2-IN-1 (XMD11-50), another creation of the Gray lab, developed to target the key Parkinson's disease target LRRK2, has been used to study potential effects of DCLK1 kinase inhibition in colorectal cancer, pancreatic cancer, head and neck cancer, and cholangiocarcinoma [16,[27][28][29][30]. However, the true role of DCLK1 inhibition in each of these studies is confounded by LRRK2-IN-1 s ability to downregulate total DCLK1 expression, which may result from inhibition of BRD4 bromodomain and/or perhaps ERK5-dependent downstream signaling.…”

Pleiotropic effects of DCLK1 in cancer and cancer stem cells

“…In a study for rectal NET, NANOG is associated with DCLK1 expression. DCLK1 serves as a new marker for rectal NET in the presence of NANOG as a gene product ( Ikezono et al, 2015 ; Broner et al, 2021 ).…”