头颈鳞癌对mTOR单一靶点药物的耐药性是临床亟待解决的难题。核糖体DNA（rDNA）含高度保守重复拷贝序列，本课题组前期研究显示rDNA拷贝数在mTOR通路过表达的多种癌症高频丢失，且显著提高DNA损伤敏感性，提示rDNA具抗应激的基因组缓冲新功能。RNA聚合酶I靶向药CX5461特异抑制rDNA转录并诱导DNA损伤，与mTOR抑制剂联合对头颈鳞癌极具治疗潜力。由此设想：头颈鳞癌rDNA拷贝丢失提高INK128与CX5461联合治疗功效。本项目利用小鼠模型和原代头颈鳞癌进行INK128与CX5461联合治疗的体内外研究，阐明其对rDNA低拷贝肿瘤的治疗敏感性；研究头颈鳞癌发展进程中基因组rDNA与染色体外rDNA环的变化规律，并鉴定相关癌症驱动基因，揭示rDNA拷贝丢失对癌症基因组稳定性、核仁结构与功能、及DNA损伤修复通路的影响，从而确立以rDNA为生物标志物的头颈鳞癌个性化治疗新方案。

The resistance of single-targeted drugs of mTOR in head and neck squamous cell carcinoma (HNSCC) is urgently needed to be solved in clinical practice. Ribosomal DNA (rDNA) contains highly conserved repetitive sequences. Our recent study showed frequent loss of rDNA copy number in multiple types of cancers with over-expression of mTOR pathway. Genomic rDNA copy loss is highly associated with increased DNA damage sensitivity. It is implicated that rDNA has a novel function to serve as the genome buffering system. CX5461, a specific inhibitor of RNA polymerase-I (RNAPI), selectively suppresses rDNA transcription and induces DNA damaging. The combination of CX5461 and mTOR inhibitor have a high potential for HNSCC treatment. Thus we hypothesize that genomic rDNA copy loss enhances combination therapy of CX5461 and mTOR inhibitor INK128 on HNSCC. In the project, we used mouse model and primary HNSCC to study the in vivo and in vitro effects of combination treatment of CX5461 and INK128. And we investigated the therapeutic sensitivity for HNSCC with lower rDNA copy number. Moreover, we will study the variation rules of genomic rDNA and extrachromosomal rDNA circle (ERC) along with tumor development of primary HNSCC. Also we will identify cancer driver gene mutations to cause the rDNA copy number variation. Furthermore, we aim to elucidate how rDNA copy loss influences cancer genome stability, nucleolar structure and function, and DNA damage and repair pathways. The study is aim to establish a new personalized therapy approach for HNSCC using rDNA as a biomarker.