Developing a Drug Repurposing Screen for Head and Neck Squamous Cell Carcinoma Using a Novel C-Rel Bioassay

Kristin Ann Altwegg,Kathryn E. King, Dvir Blivis,Ty C. Voss,Natalia J. Martinez,Wendy C. Weinberg,Mark J. Henderson

CANCER RESEARCH（2024）

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Abstract

Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Approximately 890,000 new cases are diagnosed each year, while incidence continues to rise and is anticipated to increase by 30% by 2030. HNSCC occurs most often in men in their 50-60s, although the incidence among younger individuals is increasing. Current standard of care practices include surgical resection, followed by adjuvant radiation or chemoradiation. HNSCC tumors exhibit frequent mutation of CDKN2A (22% of tumors) and TP53 (72% of tumors). Additionally, two members of the TP53 gene family, TP63 and TP73, are frequently altered in HNSCC. TP63 encodes two major isoforms, ΔNp63 which lacks the main transcription activation domain and acts as a dominant-negative inhibitor of transactivation (TA), and TAp63 (contains a p53-like TA domain). ΔNp63 is overexpressed in a majority of HNSCC tumors. Our lab has reported ΔNp63α interacts with activated c-Rel (a nuclear factor-KB family member) in HNSCC, thereby promoting uncontrolled proliferation, a key alteration in the pathogenesis of cancers. Consistent with a role in growth regulation, ΔNp63α:c-Rel complexes bind a promoter motif and repress the cyclin-dependent kinase inhibitor p21WAF1 in both human HNSCCs and normal keratinocytes overexpressing ΔNp63α. The direct relationship between ΔNp63α and activated c-Rel is observed by strong nuclear co-localization in the proliferating compartment of primary head and neck SCC. Stimulation of HNSCC cells with TNFα results in the induction of the c-Rel oncoprotein that binds to ΔNp63, displacing and inactivating the tumor suppressor TAp73 from ΔNp63-TAp73 complexes. Using western blot analysis in human HNSCC cell lines, we confirmed that stimulation with TNFα enhances nuclear c-Rel localization. We then set out to design a high throughput screening bioassay for the purpose of evaluating compounds that can inhibit c-Rel accumulation in the nucleus under TNFα stimulation. By preventing activated c-Rel from interacting with ΔNp63α in the nucleus we aim to decrease uncontrolled proliferation and restore the tumor-suppressive functionality of the ΔNp63-TAp73 complex. A 384-well immunocytochemistry assay was developed using a confocal microscopy readout and an automated image analysis algorithm to quantify nuclear translocation. The optimized assay will be used to screen the NCATS collection of approved drugs and investigational oncology agents. Top candidates will undergo further investigation in vitro, ex vivo, and in vivo to explore the possibility of repurposing the small molecules for HNSCC therapeutics. Citation Format: Kristin Ann Altwegg, Kathryn E. King, Dvir Blivis, Ty C. Voss, Natalia J. Martinez, Wendy C. Weinberg, Mark J. Henderson. Developing a drug repurposing screen for head and neck squamous cell carcinoma using a novel c-Rel bioassay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3101.

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Tumor Regression

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【要点】：本文提出了一种利用新型c-Rel生物检测方法开发头颈鳞状细胞癌药物再利用筛选技术，旨在抑制c-Rel在核内的积累，减少不受控制的细胞增殖并恢复肿瘤抑制功能。

【方法】：通过开发一种384孔免疫细胞化学检测方法，结合共聚焦显微镜读数和自动图像分析算法，来量化核易位。

【实验】：实验利用了NCATS批准药物和肿瘤学试剂的集合，通过优化的生物检测方法筛选出顶级候选药物，并在体外、离体及体内进行进一步研究，使用的数据集为人类头颈鳞状细胞癌细胞系。