Doublecortin‐like kinase 1 is a therapeutic target in squamous cell carcinoma

Standing, David; Arnold, Levi; Dandawate, Prasad; Ottemann, Brendan M.; Snyder, Vusala; Ponnurangam, Sivapriya; Sayed, Afreen Asif Ali; Subramaniam, Dharmalingam; Pugazhendhi, Srinivasan; Choudhury, Sonali; New, Jacob; Kwatra, Deep; Ramamoorthy, Prabhu; Roy, Badal C.; Shadoin, Melissa; Al‐Rajabi, Raed; O’Neil, Maura; Gunewardena, Sumedha; Ashcraft, John; Umar, Shahid; Weir, Scott J.; Tawfik, Ossama; Padhyé, Subhash; Biersack, Bernhard; Anant, Shrikant; Thomas, Sufi M.

doi:10.1002/mc.23472

Cited by 7 publications

(7 citation statements)

References 49 publications

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“…Unfavorable outcomes in HNSCC patients are often associated with locoregional invasion, a less explored aspect of the disease. Our previous work demonstrated that DCLK1 knockdown reduces cell invasion [15]. In invasive solid tumors, ECM degradation occurs through direct cell-to-matrix contact, facilitated by specialized subcellular invasive structures called invadopodia, with finger-like morphology [25].…”

Section: Resultsmentioning

confidence: 99%

“…Doublecortin like kinase 1 (DCLK1), originally characterized as a microtubule-binding protein, has predominantly been associated with cancer stem cell properties, particularly in colorectal cancer [14]. Its relevance in cancer research stems from observations, including recent findings from our research group, which highlight that inhibiting or genetically abrogating DCLK1 reduces cancer cells’ ability to degrade and invade through an ECM substrate [15]. Notably, DCLK1’s history extends beyond cancer studies and finds its origins in neurobiology.…”

Section: Introductionmentioning

confidence: 99%

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DCLK1-Mediated Regulation of Invadopodia Dynamics and Matrix Metalloproteinase Trafficking Drives Invasive Progression in Head and Neck Squamous Cell Carcinoma

Arnold,

Yap,

Jackson

et al. 2024

Preprint

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Head and neck squamous cell carcinoma (HNSCC) is a major health concern due to its high mortality from poor treatment responses and locoregional tumor invasion into life sustaining structures in the head and neck. A deeper comprehension of HNSCC invasion mechanisms holds the potential to inform targeted therapies that may enhance patient survival. We previously reported that doublecortin like kinase 1 (DCLK1) regulates invasion of HNSCC cells. Here, we tested the hypothesis that DCLK1 regulates proteins within invadopodia to facilitate HNSCC invasion. Invadopodia are specialized subcellular protrusions secreting matrix metalloproteinases that degrade the extracellular matrix (ECM). Through a comprehensive proteome analysis comparing DCLK1 control and shDCLK1 conditions, our findings reveal that DCLK1 plays a pivotal role in regulating proteins that orchestrate cytoskeletal and ECM remodeling, contributing to cell invasion. Further, we demonstrate in TCGA datasets that DCLK1 levels correlate with increasing histological grade and lymph node metastasis. We identified higher expression of DCLK1 in the leading edge of HNSCC tissue. Knockdown of DCLK1 in HNSCC reduced the number of invadopodia, cell adhesion and colony formation. Using super resolution microscopy, we demonstrate localization of DCLK1 in invadopodia and colocalization with mature invadopodia markers TKS4, TKS5, cortactin and MT1-MMP. We carried out phosphoproteomics and validated using immunofluorescence and proximity ligation assays, the interaction between DCLK1 and motor protein KIF16B. Pharmacological inhibition or knockdown of DCLK1 reduced interaction with KIF16B, secretion of MMPs, and cell invasion. This research unveils a novel function of DCLK1 within invadopodia to regulate the trafficking of matrix degrading cargo. The work highlights the impact of targeting DCLK1 to inhibit locoregional invasion, a life-threatening attribute of HNSCC.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

DCLK1-Mediated Regulation of Invadopodia Dynamics and Matrix Metalloproteinase Trafficking Drives Invasive Progression in Head and Neck Squamous Cell Carcinoma

Arnold,

Yap,

Jackson

et al. 2024

Preprint

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“…Chemoresistance of these tumors often limits the therapeutic effect of these treatments and causes unnecessary physical morbidity and economic burden to patients. Therefore, it is imperative to find targets and molecular biomarkers of chemoresistance for better treatment of HNSCC patients 7–10 …”

Section: Introductionmentioning

confidence: 99%

“…Therefore, it is imperative to find targets and molecular biomarkers of chemoresistance for better treatment of HNSCC patients. [7][8][9][10] At present, traditional Chinese medicine shows great potential in improving body immunity, reducing drug chemical toxicity, promoting tumor cell apoptosis, and enhancing the sensitivity of these tumors to chemotherapeutic drugs. HNSCC is commonly recognized as a qi and blood condensation type in Chinese medicine identification.…”

Section: Introductionmentioning

confidence: 99%

Expression of RIPK1 and FADD are associated with chemosensitivity and survival in head and heck squamous cell carcinoma via tanshinone IIA‐mediated modulation of the RIPK1‐FADD‐Caspase 8 complex

Shen,

Han,

Tan

et al. 2024

Molecular Carcinogenesis

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Tanshinone IIA (Tan IIA), a main active ingredient of salvia miltiorrhiza, has a wide range of antitumor effects, while its specific role and mechanism in head and neck squamous cell carcinomas (HNSCC) is not fully understood. Totally 59 primary HNSCC patients underwent two courses of induction chemotherapy before surgery. The association between expression of Fas‐Associated Death Domain (FADD) and receptor interacting protein kinase 1 (RIPK1) and chemotherapy resistance and survival were evaluated. The cell counting kit‐8 was used to detect the effect of Tan IIA on the activity of cisplatin in chemoresistant HNSCC cells through a series of in vitro experiments. The quantitative real‐time reverse‐transcription polymerase chain reaction, Western blot analysis and flow cytometry were used. FADD and RIPK1 expressions were differentially expressed in Chemosensitive and drug‐resistant patients. Furthermore, patients with tumors exhibiting high expression of FADD and RIPK1 had significantly greater risk for chemoresistance and mortality than patients with tumors that had low levels of these proteins. Moreover, Tan IIA reduced the expression of RIPK1 and FADD in HNSCC chemoresistant cell lines, which could increase the chemosensitivity of cisplatin and promote apoptosis. Overexpression of RIPK1 led to attenuation of therapeutic effects of Tan IIA, which were mainly realized through regulation of the RIPK1‐FADD‐Caspase 8 complex. This study is the first to demonstrate the clinical value and role of FADD and RIPK1 in the treatment of HNSCC. This work establishes the proapoptotic effects of Tan IIA and its potential to enhance chemosensitivity in HNSCC by modulating the RIPK1‐FADD‐Caspase 8 complex.

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“…Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide, contributing to 325,000 deaths and 660,000 new cases every year [1]. Despite recent therapeutic advances, the five-year survival remains below 50% [2]. There is an urgent need for development of effective small molecule inhibitors [3].…”

Section: Introductionmentioning

confidence: 99%

Acryl-3,5-bis(2,4-difluorobenzylidene)-4-piperidone targeting cellular JUN proto-oncogene, AP-1 transcription factor subunit inhibits head and neck squamous cell carcinoma progression

Arnold,

Gomez,

Barry

et al. 2023

Exploration of Targeted Anti-Tumor Therapy

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Aim: Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide with a survival rate below fifty percent. Addressing meager therapeutic options, a series of small molecule inhibitors were screened for antitumor efficacy. The most potent analog, acryl-3,5-bis(2,4-difluorobenzylidene)-4-piperidone (DiFiD; A-DiFiD), demonstrated strong cellular JUN proto-oncogene, activator protein 1 (AP-1) transcription factor subunit (JUN, c-Jun) antagonism. c-Jun, an oncogenic transcription factor, promotes cancer progression, invasion, and adhesion; high (JUN) mRNA expression correlates with poorer HNSCC survival. Methods: Four new small molecules were generated for cytotoxicity screening in HNSCC cell lines. A-DiFiD-treated HNSCC cells were assessed for cytotoxicity, colony formation, invasion, migration, and adhesion. Dot blot array was used to identify targets. Phospho-c-Jun (p-c-Jun) expression was analyzed using immunoblotting. The Cancer Genome Atlas (TCGA) head and neck cancer datasets were utilized to determine overall patient survival. The Clinical Proteomic Tumor Analysis Consortium (CPTAC) datasets interfaced with University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN) were analyzed to determine protein levels of c-Jun in HNSCC patients and correlate levels with patient. Results: Of the small molecules tested, A-DiFiD was the most potent in HNSCC lines, while demonstrating low half-maximal drug inhibitory concentration (IC50) in non-malignant Het-1A cells. Additionally, A-DiFiD abrogated cell invasion, migration, and colony formation. Phospho-kinase in vitro array demonstrated A-DiFiD reduced p-c-Jun. Likewise, a time dependent reduction in p-c-Jun was observed starting at 3 min post A-DiFiD treatment. TCGA Firehose Legacy vs. recurrent and metastatic head and neck cancer reveal a nearly 3% DNA amplification in recurrent/metastatic tumor compared to below 1% in primary tumors that had no lymph node metastasis. CPTAC analysis show higher tumor c-Jun levels compared to normal. Patients with high JUN expression had significantly reduced 3-year survival. Conclusions: A-DiFiD targets c-Jun, a clinical HNSCC driver, with potent anti-tumor effects.

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Doublecortin‐like kinase 1 is a therapeutic target in squamous cell carcinoma

Cited by 7 publications

References 49 publications

DCLK1-Mediated Regulation of Invadopodia Dynamics and Matrix Metalloproteinase Trafficking Drives Invasive Progression in Head and Neck Squamous Cell Carcinoma

DCLK1-Mediated Regulation of Invadopodia Dynamics and Matrix Metalloproteinase Trafficking Drives Invasive Progression in Head and Neck Squamous Cell Carcinoma

Expression of RIPK1 and FADD are associated with chemosensitivity and survival in head and heck squamous cell carcinoma via tanshinone IIA‐mediated modulation of the RIPK1‐FADD‐Caspase 8 complex

Acryl-3,5-bis(2,4-difluorobenzylidene)-4-piperidone targeting cellular JUN proto-oncogene, AP-1 transcription factor subunit inhibits head and neck squamous cell carcinoma progression

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