Wu Chi-Sheng, Li Hsin-Pai, Hsieh Chia-Hsun, Lin Yu-Tsun, Yi-Feng Chang Ian, Chung An-Ko, Huang Yenlin, Ueng Shir-Hwa, Hsiao Yung-Chin, Chien Kun-Yi, Luo Ji-Dung, Chen Chia-Hua, Liao Wei-Chao, Hung Jui-Lung, Yuan Sheng-Ning, OuYang Chun-Nan, Chiang Wei-Fan, Chien Chih-Yen, Chuang Hui-Ching, Chu Lichieh Julie, Liu Hsuan, Yang Chia-Yu, Robles Ana I, Rodriguez Henry, Lin Hsi-Hsien, Yang Huang-Yu, Hsueh Chuen, Chang Kai-Ping, Yu Jau-Song, Chang Yu-Sun
Molecular Medicine Research Center, Chang Gung University, Taoyuan City, 33302, Taiwan; Department of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan City, 33305, Taiwan.
Molecular Medicine Research Center, Chang Gung University, Taoyuan City, 33302, Taiwan; Department of Microbiology and Immunology, Chang Gung University, Taoyuan City, 33302, Taiwan; Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, at Linkou, Taoyuan City, 33305, Taiwan.
Cancer Lett. 2025 Apr 1;614:217482. doi: 10.1016/j.canlet.2025.217482. Epub 2025 Jan 20.
Oral cavity squamous cell carcinoma (OSCC), a leading subtype of head and neck cancer, exhibits high global incidence and mortality rates. Despite advancements in surgery and radiochemotherapy, approximately one-third of patients experience relapse. To improve current targeted and immunotherapy strategies for recurrent OSCC, we conducted multi-omics analyses on pretreatment OSCC samples (cohorts 1 and 2, n = 137) and identified A3A and EGFR, both at the RNA and protein levels, as inversely expressed markers for patient stratification and response prediction. Survival analysis demonstrated that elevated A3A or PD-L1 expression levels correlated to improved responses to anti-PD-1 therapy in patients (cohort 3a, n = 50, IHC). In contrast, high RRAS expression (cohort 4, n = 252, qRT-PCR) was significantly associated with OSCC recurrence. Cell-based experiments revealed that RRAS was involved in radiotherapy and cisplatin resistance through the EGFR/RRAS/AKT/ERK signaling pathway. In OSCC patient-derived xenograft (PDX) mouse models, treatments with cisplatin and cetuximab (anti-EGFR) effectively reduced tumor size in EGFR-high-derived (#34) but not A3A-high-derived (#22) PDX tumors. Our study demonstrated that A3A-high tumors were immune-hot and responsive to anti-PD-1 therapy, whereas EGFR-high tumors exhibited chr.7p11.2 gains and DNA repair alterations. Additionally, RRAS-high tumors were associated with OSCC recurrence via AKT and ERK phosphorylation and demonstrate improved clinical outcomes with cetuximab therapy (cohort 3b, n = 49, IHC). This study emphasizes the significance of A3A and EGFR expression levels in OSCC patient stratification and precision therapy, suggesting the use of anti-PD-1 or anti-EGFR treatments, respectively based on these biomarkers. Furthermore, RRAS emerges as a novel prognostic marker for local recurrence.
口腔鳞状细胞癌（OSCC）是头颈癌的主要亚型，在全球范围内具有较高的发病率和死亡率。尽管手术及放化疗取得了进展，但仍有大约三分之一的患者会复发。为了改进复发性OSCC的现有靶向治疗和免疫治疗策略，我们对治疗前的OSCC样本（队列1和队列2，n = 137）进行了多组学分析，并在RNA和蛋白质水平上确定了A3A和EGFR作为用于患者分层和反应预测的反向表达标志物。生存分析表明，A3A或PD-L1表达水平升高与患者对抗PD-1治疗的反应改善相关（队列3a，n = 50，免疫组化）。相反，高RRAS表达（队列4，n = 252，定量逆转录聚合酶链反应）与OSCC复发显著相关。基于细胞的实验表明，RRAS通过EGFR/RRAS/AKT/ERK信号通路参与放疗和顺铂耐药。在OSCC患者来源的异种移植（PDX）小鼠模型中，顺铂和西妥昔单抗（抗EGFR）治疗有效减小了EGFR高表达来源（#34）的PDX肿瘤大小，但对A3A高表达来源（#22）的PDX肿瘤无效。我们的研究表明，A3A高表达的肿瘤具有免疫活性，对抗PD-1治疗有反应，而EGFR高表达的肿瘤表现出7号染色体短臂11.2区域扩增和DNA修复改变。此外，RRAS高表达的肿瘤通过AKT和ERK磷酸化与OSCC复发相关，西妥昔单抗治疗可改善临床结局（队列3b，n = 49，免疫组化）。本研究强调了A3A和EGFR表达水平在OSCC患者分层和精准治疗中的重要性，表明可分别基于这些生物标志物使用抗PD-1或抗EGFR治疗。此外，RRAS成为局部复发的新型预后标志物。
