1 Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
J Dent Res. 2018 Jun;97(6):635-644. doi: 10.1177/0022034518759068. Epub 2018 Feb 28.
Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer worldwide and in the United States. OSCC remains a major cause of morbidity and mortality in patients with head and neck cancers. Tobacco and alcohol consumption alone or with chewing betel nut are potential risk factors contributing to the high prevalence of OSCC. Multimodality therapies, including surgery, chemotherapy, biologic therapy, and radiotherapy, particularly intensity-modulated radiotherapy (IMRT), are the current treatments for OSCC patients. Despite recent advances in these treatment modalities, the overall survival remains poor over the past years. Recent data from whole-exome sequencing reveal that TP53 is commonly mutated in human papillomavirus-negative OSCC patients. Furthermore, these data stressed the importance of the TP53 gene in suppressing the development and progression of OSCC. Clinically, TP53 mutations are largely associated with poor survival and tumor resistance to radiotherapy and chemotherapy in OSCC patients, which makes the TP53 mutation status a potentially useful molecular marker prognostic and predictive of clinical response in these patients. Several forms of DNA damage have been shown to activate p53, including those generated by ionizing radiation and chemotherapy. The DNA damage stabilizes p53 in part via the DNA damage signaling pathway that involves sensor kinases, including ATM and ATR and effector kinases, such as Chk1/2 and Wee1, which leads to posttranscriptional regulation of a variety of genes involved in DNA repair, cell cycle control, apoptosis, and senescence. Here, we discuss the link of TP53 mutations with treatment outcome and survival in OSCC patients. We also provide evidence that small-molecule inhibitors of critical proteins that regulate DNA damage repair and replication stress during the cell cycle progression, as well as other molecules that restore wild-type p53 activity to mutant p53, can be exploited as novel therapeutic approaches for the treatment of OSCC patients bearing p53 mutant tumors.
口腔鳞状细胞癌（OSCC）是全球和美国最常见的口腔癌类型。OSCC 仍然是头颈部癌症患者发病率和死亡率的主要原因。单独或与咀嚼槟榔一起使用烟草和酒精是导致 OSCC 高发的潜在危险因素。包括手术、化疗、生物治疗和放疗在内的多模态治疗方法，特别是强度调制放疗（IMRT），是 OSCC 患者的当前治疗方法。尽管这些治疗方式最近有所进展，但过去几年来总体生存率仍然很差。全外显子组测序的最新数据显示，TP53 在人乳头瘤病毒阴性的 OSCC 患者中经常发生突变。此外，这些数据强调了 TP53 基因在抑制 OSCC 发展和进展中的重要性。临床上，TP53 突变与 OSCC 患者的生存不良和对放疗和化疗的肿瘤耐药性密切相关，这使得 TP53 突变状态成为这些患者潜在有用的分子标志物，可预测预后和临床反应。已经显示几种形式的 DNA 损伤可激活 p53，包括由电离辐射和化疗产生的损伤。DNA 损伤通过涉及传感器激酶（包括 ATM 和 ATR）和效应激酶（如 Chk1/2 和 Wee1）的 DNA 损伤信号通路部分稳定 p53，从而导致参与 DNA 修复、细胞周期控制、凋亡和衰老的各种基因的转录后调节。在这里，我们讨论了 TP53 突变与 OSCC 患者治疗结果和生存的关系。我们还提供了证据，表明在细胞周期进展过程中调节 DNA 损伤修复和复制应激的关键蛋白的小分子抑制剂，以及其他将野生型 p53 活性恢复到突变型 p53 的分子，可以被开发为治疗携带突变型 p53 肿瘤的 OSCC 患者的新型治疗方法。
