A molecular signature of well-differentiated oral squamous cell carcinoma reveals a resistance mechanism to metronomic chemotherapy and novel therapeutic candidates
A molecular signature of well-differentiated oral squamous cell carcinoma reveals a resistance mechanism to metronomic chemotherapy and novel therapeutic candidates
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DOI：
10.1080/1061186x.2021.1929256
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发表时间：
2021-05-26
影响因子：
4.5
通讯作者：
Kinjo, Takao
中科院分区：
文献类型：
--
作者：
Kina, Shinichiro;Kawabata-Iwakawa, Reika;Kinjo, Takao
分化良好的头颈部鳞状细胞癌（HNSCC）约占所有HNSCC的10%，虽然这些病例与手术后的良好预后相关，但这些病例对化疗具有抗性。我们设计了一项回顾性研究，以评估组织分化对接受手术或节拍式新辅助化疗的舌鳞状细胞癌（TSCC）患者的影响。节拍式新辅助化疗显著改善了低分化或中分化肿瘤患者的总生存期，但对高分化肿瘤患者无明显影响。癌症基因组图谱（TCGA）的分析表明，FAT 1突变显着富集在更分化的HNSCC中，而ASPM突变显着富集在低分化的HNSCC中。有趣的是，Wnt/β-catenin通路在分化良好的HNSCC中被激活。高分化口腔鳞癌细胞系中活性β-连环蛋白转位至细胞核。Wnt抑制剂Wnt 974与甲氨蝶呤对分化良好的口腔鳞状细胞癌（OSCC）细胞具有协同杀伤作用。TCGA数据分析揭示了高分化HNSCC患者的特征，这些患者没有从节拍式新辅助化疗中获益，这表明可能有新的疾病分类学和治疗候选物用于改善HNSCC患者的生存率。Wnt抑制剂联合化疗可协同杀死分化良好的口腔鳞癌，使其成为有希望的治疗候选者。
Well-differentiated head and neck squamous cell carcinoma (HNSCC), accounts for approximately 10% of all HNSCCs and, while these cases are associated with good prognosis after surgery, these are resistant to chemotherapy. Here we designed a retrospective study to evaluate the effects of histological differentiation on tongue squamous cell carcinoma (TSCC) patients undergoing surgery or metronomic neoadjuvant chemotherapy. The metronomic neoadjuvant chemotherapy significantly improved overall survival of patients with poorly or moderately differentiated tumour, but not those with well-differentiated tumour. Analysis of the Cancer Genome Atlas (TCGA) showed that FAT1 mutations were significantly enriched in more differentiated HNSCC while ASPM mutations were significantly enriched among the poorly differentiated HNSCC. Interestingly, Wnt/beta-catenin pathway was activated in well-differentiated HNSCC. Active beta-catenin is translocated to the nucleus in the well-differentiated oral squamous cell carcinoma cell lines. Wnt inhibitor, Wnt974, were synergistic with methotrexate in killing well-differentiated oral squamous cell carcinoma (OSCC) cell lines. TCGA data analyses reveal a signature in patients with well-differentiated HNSCC who have no benefits from metronomic neoadjuvant chemotherapy, suggesting that there might be novel nosology and therapeutic candidates for improving HNSCC patient survival. Well-differentiated OSCC is synergistically killed by combination chemotherapy with Wnt inhibitor, making it promising therapeutic candidates.