Targeted therapy revolutionizes the treatment of non-small-cell lung cancer (NSCLC), harboring molecular change. Epidermal growth factor receptor(EGFR) mutations play a crucial role in the development of NSCLC, serving as a pivotal factor in its pathogenesis. We elucidated the mechanisms of resistance and potential therapeutic strategies in NSCLC resistant to the EGFR-tyrosine kinase inhibitor (EGFR-TKI). This is achieved by identifying rare missense variants through whole exome sequencing (WES). The goal is to enhance our understanding, identify biomarkers, and lay the groundwork for targeted interventions, thereby offering hope for an improved NSCLC treatment landscape. We conducted WES analysis on 16 NSCLC samples with EGFR-TKI-resistant NSCLC obtained from SRA-NCBI (PRJEB50602) to reveal genomic profiles within the EGFR-TKI. Our findings showed that 48% of the variants were missense, and after filtering with the Ensembl variant effect predictor, 53 rare missense variants in 23 genes were identified as highly deleterious. Further examination using pathogenic tools like PredictSNP revealed 12 deleterious rare missense variants in 7 genes: ZNF717, PSPH, ESRRA, SEMA3G, PTPN7, CAVIN4, and MYBBP1A. Molecular dynamics simulation (MDS) suggested that the L385P variant alters the structural flexibility of ESRRA, potentially leading to unfolding of ERRα proteins. This could impact their function and alter ERRα expression. These insights from MDS enhance our understanding of the structural and dynamic consequences of the L385P ESRRA variant and provide valuable implications for subsequent therapeutic considerations and targeted interventions.

中文翻译：

---

通过全外显子组测序解读罕见错义变异对 EGFR-TKI 耐药的非小细胞肺癌的影响：一种计算方法

靶向治疗彻底改变了非小细胞肺癌 (NSCLC) 的治疗，带来了分子变化。表皮生长因子受体（EGFR）突变在NSCLC的发生发展中发挥着至关重要的作用，是其发病机制的关键因素。我们阐明了对 EGFR 酪氨酸激酶抑制剂 (EGFR-TKI) 耐药的 NSCLC 的耐药机制和潜在治疗策略。这是通过全外显子组测序 (WES) 识别罕见的错义变异来实现的。目标是增强我们的理解，识别生物标志物，并为有针对性的干预措施奠定基础，从而为改善 NSCLC 治疗前景带来希望。我们对从 SRA-NCBI (PRJEB50602) 获得的 16 个 EGFR-TKI 耐药 NSCLC 样本进行了 WES 分析，以揭示 EGFR-TKI 内的基因组图谱。我们的研究结果表明，48% 的变异是错义变异，经过 Ensembl 变异效应预测器过滤后，23 个基因中的 53 个罕见错义变异被鉴定为高度有害。使用 PredictSNP 等致病工具进行的进一步检查揭示了 7 个基因中的 12 种有害的罕见错义变异：ZNF717、PSPH、ESRRA、SEMA3G、PTPN7、CAVIN4和MYBBP1A。分子动力学模拟 (MDS) 表明 L385P 变体改变了 ESRRA 的结构灵活性，可能导致 ERRα 蛋白的解折叠。这可能会影响它们的功能并改变 ERRα 表达。 MDS 的这些见解增强了我们对 L385P ESRRA 变异的结构和动态后果的理解，并为后续的治疗考虑和有针对性的干预措施提供了宝贵的启示。