St John of God Hospital, Suite C202, 12 Salvado Road, Subiaco, 6008, Australia.
Department of Medicine, St Vincent's Hospital, Melbourne Medical School, University of Melbourne, Melbourne, Australia.
Med Oncol. 2017 Sep 6;34(10):175. doi: 10.1007/s12032-017-1031-1.
Resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) against EGFR mutant lung adenocarcinoma develops after a median of nine to thirteen months. Upregulation of the interleukin-6 (IL-6)/Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway may be a potential source of resistance to EGFR TKIs. We undertook a detailed assessment of the IL-6/JAK1/phosphorylated STAT3 (pSTAT3) pathway in resected lung adenocarcinoma specimens, with special interest in whether the presence of an EGFR mutation enriched for pSTAT3 positivity. Tumours from 143 patients with resected lung adenocarcinoma were assessed. EGFR and KRAS mutation status were scanned for with high-resolution melting and confirmed by polymerase chain reaction. Immunohistochemisty (IHC) was performed for IL-6, gp130, JAK1 and pSTAT3. Two methods for assigning IHC positivity were assessed (the presence of any positivity, and the presence of positivity at an H score >40). We found statistically significant associations between IL-6, JAK1 and pSTAT3 measured by IHC, consistent with the activation of the pathway in clinical specimens. No relationship was demonstrated between members of this pathway and oncogenic mutations in EGFR or KRAS. However, a proportion of tumours with EGFR mutations showed staining for IL-6, JAK1 and pSTAT3. No correlations with clinicopathologic features or survival outcomes were found for IL-6, JAK1 or pSTAT3 staining. The presence of EGFR or KRAS mutations did not enrich for the activation of IL-6, JAK1 or pSTAT3. pSTAT3 may still play a role in resistance to EGFR TKIs in clinical practice.
表皮生长因子受体 (EGFR) 酪氨酸激酶抑制剂 (TKI) 对 EGFR 突变型肺腺癌的耐药性在 9 至 13 个月后出现。白细胞介素-6 (IL-6)/Janus 激酶 (JAK)/信号转导和转录激活因子 (STAT) 途径的上调可能是 EGFR TKI 耐药的潜在来源。我们对切除的肺腺癌标本中的 IL-6/JAK1/磷酸化 STAT3 (pSTAT3) 途径进行了详细评估，特别关注 EGFR 突变是否会使 pSTAT3 阳性率增加。评估了 143 例切除的肺腺癌患者的肿瘤。使用高分辨率熔解和聚合酶链反应扫描 EGFR 和 KRAS 突变状态。进行免疫组织化学 (IHC) 检测 IL-6、gp130、JAK1 和 pSTAT3。评估了两种分配 IHC 阳性的方法（存在任何阳性和 H 评分>40 的阳性）。我们发现 IHC 测量的 IL-6、JAK1 和 pSTAT3 之间存在统计学显著关联，这与临床标本中该途径的激活一致。该途径的成员与 EGFR 或 KRAS 致癌突变之间没有关系。然而，一部分具有 EGFR 突变的肿瘤显示出 IL-6、JAK1 和 pSTAT3 的染色。IL-6、JAK1 或 pSTAT3 染色与临床病理特征或生存结果无相关性。EGFR 或 KRAS 突变的存在并没有使 IL-6、JAK1 或 pSTAT3 的激活富集。pSTAT3 在临床上可能仍然在 EGFR TKI 耐药中发挥作用。
