Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China.
Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong Province, China.
Lab Invest. 2019 Apr;99(4):568-576. doi: 10.1038/s41374-018-0164-y. Epub 2018 Dec 14.
Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptors (EGFR) significantly prolong the survival of lung adenocarcinoma patients with sensitizing EGFR mutations. Unfortunately, 10-30% patients do not show objective responses to EGFR-TKIs, and undergo rapid disease progression during the EGFR-TKIs therapy. Single nucleotide polymorphisms (SNPs) in mature microRNA (miRNA) sequences may influence target site interactions and modulate downstream pathways, such as the EGFR pathway. For this reason, we hypothesized that miRNA SNPs may impact the prognosis of lung adenocarcinoma patients after EGFR-TKI treatment. By systematically screening of the miRbase and the 1000 genomes project databases, we successfully identified five mature miRNA SNPs. Genotypes were determined in two independent cohorts (Hubei and Shandong cohorts) that include 319 EGFR-TKI treated stage IIIB/IV patients. The impact of miR-608 and miR-4513 on the drug sensitivity of gefitinib was examined in lung adenocarcinoma cells. miR-608 rs4919510 or miR-4513 rs2168518 significantly contributed to the progression-free survival (PFS) in the Hubei cohort (hazard ratio [HR] = 0.63, confidence interval [CI] = 0.49-0.81, P = 3.0 × 10 or HR = 0.46, 95% CI = 0.31-0.67, P = 8.0 × 10). These observations were further validated in the Shandong cohort (P = 0.005 or P = 0.001). Similarly, the miR-608 rs4919510 CC genotype or the miR-4513 rs2168518 GA genotype was significantly associated with decreased death risk after gefitinib treatment, compared with the rs4919510 GG genotype (Hubei cohort: P = 5.0 × 10; Shandong cohort: P = 0.004) or the rs2168518 GG genotype (P = 4.9 × 10; P = 0.002). Consistently, miR-608 significantly increased the anti-proliferation effect of gefitinib in both lung adenocarcinoma PC9 and H1299 cells, whereas miR-4513 increased cells' resistance to gefitinib. Our findings suggest that miR-608 and miR-4513 SNPs are independent candidate biomarkers to predict lung adenocarcinoma patients' survival after EGFR-TKIs treatment. These miRNAs and polymorphisms provide clinical potential in patient-tailored treatment decision-making.
酪氨酸激酶抑制剂（TKIs）针对表皮生长因子受体（EGFR）显著延长了具有敏感 EGFR 突变的肺腺癌患者的生存时间。不幸的是，10-30%的患者对 EGFR-TKIs 没有表现出客观的反应，并且在 EGFR-TKIs 治疗期间疾病迅速进展。成熟 microRNA（miRNA）序列中的单核苷酸多态性（SNP）可能会影响靶位相互作用并调节下游途径，如 EGFR 途径。基于此，我们假设 miRNA SNP 可能会影响 EGFR-TKI 治疗后肺腺癌患者的预后。通过系统筛选 miRbase 和 1000 基因组计划数据库，我们成功鉴定了五个成熟 miRNA SNP。在包括 319 名接受 EGFR-TKI 治疗的 IIIB/IV 期患者的两个独立队列（湖北和山东队列）中确定了基因型。在肺腺癌细胞中，miR-608 和 miR-4513 对吉非替尼的药物敏感性的影响进行了研究。miR-608 rs4919510 或 miR-4513 rs2168518 显著影响湖北队列的无进展生存期（PFS）（风险比[HR] = 0.63，置信区间[CI] = 0.49-0.81，P = 3.0×10 或 HR = 0.46，95% CI = 0.31-0.67，P = 8.0×10）。这些观察结果在山东队列中得到了进一步验证（P = 0.005 或 P = 0.001）。同样，与 rs4919510 GG 基因型相比，miR-608 rs4919510 CC 基因型或 miR-4513 rs2168518 GA 基因型与吉非替尼治疗后死亡风险降低显著相关（湖北队列：P = 5.0×10；山东队列：P = 0.004）或 rs2168518 GG 基因型（P = 4.9×10；P = 0.002）。一致地，miR-608 显著增加了肺腺癌细胞 PC9 和 H1299 中吉非替尼的抗增殖作用，而 miR-4513 增加了细胞对吉非替尼的耐药性。我们的研究结果表明，miR-608 和 miR-4513 SNP 是预测 EGFR-TKIs 治疗后肺腺癌患者生存的独立候选生物标志物。这些 miRNA 和多态性为基于患者的治疗决策提供了临床潜力。
