UBXN11单核苷酸多态性作为EGFR敏感突变肺腺癌术后辅助靶向治疗新的疗效预测标志物及其耐药机制研究

本课题组前期研究发现R0切除的IIIA期EGFR敏感突变NSCLC患者，和辅助化疗相比，术后辅助靶向治疗能显著延长无疾病生存期，总生存也呈获益趋势（EVAN研究）。即便同为术后辅助靶向治疗人群，疗效亦存在明显差异。前期将该临床研究的组织和血液标本行全外显子测序，结果显示UBXN11的单核苷酸多态性（SNP）与EGFR敏感突变的肺腺癌术后辅助靶向治疗更差的DFS相关，短期出现局部进展或远处转移。UBXN11 SNP是影响术后辅助靶向治疗的关键疗效预测因素，在介导EGFR敏感突变患者对EGFR-TKI耐药可能发挥关键作用，但具体耐药机制尚不明确。我们的假设是UBXN11 SNP通过影响与RND1结合，导致RhoA活性调控失衡进而影响肺癌细胞的迁移，介导靶向治疗耐药发生。本课题拟进一步探索UBXN11 SNP影响EGFR-TKI疗效的分子机制，便于精确筛选靶向治疗获益人群，解决临床关键问题。

Our previous study found that compared with adjuvant chemotherapy, adjuvant targeted therapy can significantly prolong disease-free survival and overall survival of patients with stage IIIA EGFR sensitive mutation NSCLC after R0 resection (Evan study). There are significant differences in the efficacy even among the patients with postoperative adjuvant targeted therapy. The results showed that the single nucleotide polymorphism (SNP) of UBXN11 was associated with worse DFS after adjuvant targeted therapy in lung adenocarcinoma with EGFR sensitive mutation, and short-term local progression or distant metastasis occurred. UBXN11 SNP is a key predictor of postoperative adjuvant targeted therapy. It may play a key role in mediating EGFR TKI resistance in patients with EGFR sensitive mutations, but the specific mechanism of resistance is not clear. Our hypothesis is that UBXN11 SNP affects the binding of Rnd1, leading to the imbalance of RhoA activity regulation, and then affects the migration of lung cancer cells, and mediates the occurrence of drug resistance to targeted therapy. This project aims to further explore the molecular mechanism of UBXN11 SNP affecting the efficacy of EGFR-TKI, so as to facilitate the accurate screening of targeted treatment beneficiaries and solve key clinical problems.