Bourdier Solenne, Fisch Anne-Sophie, Alp Keziban Merve, Das Ridhima, Mertins Philipp, Tinhofer Ingeborg
Department of Radiooncology and Radiotherapy, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117, Berlin, Germany.
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, 13092, Berlin, Germany.
Sci Rep. 2025 Jan 10;15(1):1555. doi: 10.1038/s41598-025-85214-9.
Human papilloma virus-negative head and neck squamous cell carcinoma (HNSCC) frequently harbors 11q13 amplifications. Among the oncogenes at this locus, CCND1 and ANO1 are linked to poor prognosis; however, their individual roles in treatment resistance remain unclear. The impact of Cyclin D1 and Ano1 overexpression on survival was analyzed using the TCGA HNSCC dataset and a Charité cohort treated with cisplatin (CDDP)-based radiochemotherapy. High Ano1 expression was primarily associated with poor overall survival in both datasets. The effects of CCND1 and ANO1 knockdown (KD) on radio- and drug sensitivity, along with changes in global protein expression, cell viability, growth, and DNA repair, were studied in an 11q13-amplified HNSCC cell line model of primary cisplatin resistance. Unique pathway alterations- VEGF in CCND1 KD and the Rho GTPase cycle in ANO1 KD- were observed, along with shared changes like DNA damage and cell cycle dysregulation. Silencing CCND1 or ANO1 increased CDDP sensitivity, while only ANO1 silencing increased radiosensitivity. Copanlisib and afatinib were identified as promising candidates for combination therapy of 11q13-amplified HNSCC tumors. We demonstrated a predominant role for Ano1 in treatment resistance in Cyclin D1Ano1 HNSCC tumors and identified novel potential treatment combinations for this high-risk patient group.
人乳头瘤病毒阴性头颈部鳞状细胞癌（HNSCC）常伴有11q13扩增。在该位点的致癌基因中，CCND1和ANO1与预后不良有关；然而，它们在治疗耐药性中的个体作用仍不清楚。使用TCGA HNSCC数据集和接受基于顺铂（CDDP）的放化疗的夏里特队列分析了细胞周期蛋白D1和Ano1过表达对生存的影响。在两个数据集中，高Ano1表达主要与总体生存不良相关。在原发性顺铂耐药的11q13扩增HNSCC细胞系模型中，研究了CCND1和ANO1敲低（KD）对放射敏感性和药物敏感性的影响，以及全球蛋白质表达、细胞活力、生长和DNA修复的变化。观察到独特的通路改变——CCND1 KD中的VEGF和ANO1 KD中的Rho GTPase循环——以及DNA损伤和细胞周期失调等共同变化。沉默CCND1或ANO1可增加CDDP敏感性，而只有ANO1沉默可增加放射敏感性。库潘尼西和阿法替尼被确定为11q13扩增HNSCC肿瘤联合治疗的有前景的候选药物。我们证明了Ano1在细胞周期蛋白D1/Ano1 HNSCC肿瘤的治疗耐药中起主要作用，并为这一高危患者群体确定了新的潜在治疗组合。
