miR-608 and miR-4513 significantly contribute to the prognosis of lung adenocarcinoma treated with EGFR-TKIs.

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.