COL7A1-UCN2嵌合体介导JAK-PI3K-STAT信号轴调控EGFR磷酸化在头颈鳞癌多靶耐药敏感性中的机制研究

对于头颈鳞癌，化疗及联合靶向药物治疗是除手术外重要治疗手段，但多重耐药会降低治疗有效率，导致预后较差，其发生机制目前仍缺乏深入研究。申请人前期已经对Col7a1-UCN2嵌合体阳性头颈鳞癌样本进行转录组测序联合Cas9全基因组慢病毒筛选文库研究，明确PI3K和HDAC通路与肿瘤耐药相关；又利用EGFR 、PI3K及HDAC靶向抑制药Erlotinib 、Copanlisi 及Vorinostat进行联合多靶试验，探究药物协同作用，通过JAK-PI3K-STAT轴调节EGFR关键位点磷酸化，增加EGFR靶向药抗肿瘤细胞活性作用机制；后续将结合单细胞测序绘制肿瘤微环境图谱，解析肿瘤异质性特征基因表达与信号通路，挖掘与耐药和预后相关的潜在分子标志物，为头颈鳞癌精准分子分型提供理论依据；并对提高药物敏感性减少耐药性的调控机制进行阐述，进而优化治疗方案，最终为头颈鳞癌的个体化治疗提供新的思路。

For head and neck squamous cell carcinoma（HNSCC）, chemotherapy and target therapy are still the first-line options. Drug resistance of HNSCC may lead to malignant progression and poor prognosis, while the mechanism remains to be studied. This project was focused on Col7a1-UCN2 chimera-positive HNSCC samples. Firstly, transcriptome sequencing and Cas9 whole-genome lentiviral library screening were used to establish the relationship between PI3K, HDAC signaling pathways and tumor drug resistance. Secondly, Erlotinib(EGFR inhibitor), Copanlisi(PI3K inhibitor) and Vorinostat(HDAC inhibitor) were applied to explore the drug synergistic effects to enhance anti-tumor efficiency of EGFR target therapy by regulating EGFR phosphorylation via JAK-PI3K-STAT signaling pathways. Thirdly, single-cell sequencing was employed to map tumor microenvironment. Together with clinical data, characteristic gene expression and signaling pathways were analyzed to screen out potential molecular markers for drug resistance and clinical prognosis, which could provide theoretical guideline for precise molecular typing of HNSCC. Furthermore, the mechanical studies on increasing drug sensitivity and reducing drug resistance would optimize clinical treatments and provide novel ideas for HNSCC individualized therapy.