Background and objective: The significant efficacy of tyrosine kinase inhibitors (TKIs) has been approved for advanced non-small cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations. No clear evidence exists that EGFR-L861Q is sensitive to TKIs, and the best treatment for NSCLC patients with EGFR-L861Q mutation is undetermined. This study aims to discuss the best treatment for advanced NSCLC patients with EGFR-L861Q mutation by analyzing the differences among the structures of wild-type EGFR, activating mutant EGFR-L858R, and EGFR-L861Q mutation.
Methods: The protein structures of wild-type EGFR were reconstructed. EGFR-L858R and EGFR-L861Q mutation were activated. The differences among the three kinds of protein conformation were analyzed using homologous modeling technique.
Results: The structure of EGFR-L858R and wild-type EGFR exhibited notable distinctions. The structure of EGFR-L861Q mutation was different compared with wild-type EGFR and activating mutant EGFR-L858R protein conformations. NSCLC patients with EGFR-L861Q mutation were given chemotherapy as the first-line of therapy, and TKIs were applied to maintain treatment when the tumor is unchanged. Effect evaluation result was improved when the lung computed tomography lesions were reviewed.
Conclusions: The analysis of the protein conformation of EGFR-L861Q mutation and the curative effect of chemotherapy with TKIs could help predict the sensitivity of EGFR-L861Q to TKIs. Combining the analysis with a clinical case, maintenance treatment with TKIs may achieve satisfactory curative effect in advanced NSCLC patients who have achieved disease control after first-line chemotherapy.
背景与目的 对于伴表皮生长因子受体（epidermal growth factor receptor, EGFR）敏感型突变的晚期非小细胞肺癌（non-small cell lung cancer, NSCLC）患者，小分子酪氨酸激酶抑制剂（tyrosine kinase inhibitor, TKI）的显著疗效众所周知。但对于晚期NSCLC伴EGFR-L861Q突变的患者，TKIs治疗是否敏感，治疗时机和治疗方案该如何选择，至今尚无确切的循证医学证据。本研究旨在通过分析EGFR-L861Q与敏感突变型EGFR-L858R及野生型EGFR蛋白质空间构象的差异，结合临床实例探讨晚期NSCLC伴EGFR-L861Q突变患者的最佳治疗方案。方法 利用同源模建重建野生型EGFR、敏感突变型EGFR-L858R及突变型EGFR-L861Q蛋白质的空间构象，并分析这三种空间构象之间的差异。结果 敏感突变型EGFR-L858R与野生型EGFR蛋白质的空间构象差异显著。突变型EGFR-L861Q与敏感突变型EGFR-L858R及野生型EGFR的蛋白质空间构象均不完全相同。在临床中，我们总结了1例晚期NSCLC伴EGFR-L861Q突变的患者，应用化疗作为一线治疗，当肿瘤不再缩小时，换用TKIs维持治疗，复查肺部计算机断层扫描（computed tomography, CT），肿瘤较前相比进一步缩小。结论 通过对突变型EGFR-L861Q的蛋白质空间构象进行分析比对，结合临床实例，对于晚期NSCLC伴EGFR-L861Q突变的患者，一线化疗后达到疾病控制时，换用TKIs维持治疗，可能获得令人满意的临床疗效。.