For non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations, the initial therapeutic interventions will have crucial impacts on their clinical outcomes. Drug tolerant factors reportedly have an impact on EGFR-tyrosine kinase inhibitor sensitivity. This prospective study investigated the impacts of drug tolerant-related protein expression in tumors based on the efficacy of osimertinib in the first-setting of EGFR-mutated advanced NSCLC patients. A total of 92 patients with EGFR-mutated advanced or postoperative recurrent NSCLC were analyzed and treated with osimertinib at 14 institutions in Japan. AXL, p53, and programmed death-ligand 1 (PD-L1) expression in patient tumors was determined using immunohistochemistry. The AXL signaling pathway was investigated using a cell line-based assay and AXL-related gene expression in The Cancer Genome Atlas (TCGA) database. High levels of AXL and positive-p53 expression were detected in 26.1% and 53.3% of the pretreatment EGFR-mutated NSCLC tumors, respectively. High AXL expression levels were significantly associated with a shorter progression-free survival compared with low AXL expression levels, irrespective of the EGFR activating mutation status (p = 0.026). Cell line-based assays indicated that the overexpression of AXL protein accelerated PD-L1 expression, which induced insensitivity to osimertinib. In the TCGA database, AXL RNA levels were positively correlated with PD-L1 expression in the lung adenocarcinoma cohort. The results show that high AXL expression levels in tumors impact clinical predictions when using osimertinib to treat EGFR-mutated NSCLC patients. Trial Registration: UMIN000043942.

中文翻译：

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未经治疗的 EGFR 突变非小细胞肺癌中的高水平 AXL 表达对奥希替尼的使用产生负面影响

对于表皮生长因子受体 ( EGFR ) 突变的非小细胞肺癌 (NSCLC) 患者，初始治疗干预将对其临床结果产生至关重要的影响。据报道，耐药因素会影响 EGFR 酪氨酸激酶抑制剂的敏感性。这项前瞻性研究基于奥希替尼在EGFR突变的晚期 NSCLC 患者的首次治疗中的疗效，调查了肿瘤中耐药相关蛋白表达的影响。EGFR共92例在日本的 14 家机构中对突变的晚期或术后复发 NSCLC 进行了分析，并使用奥希替尼进行了治疗。使用免疫组织化学确定患者肿瘤中的 AXL、p53 和程序性死亡配体 1 (PD-L1) 表达。使用基于细胞系的测定和癌症基因组图谱 (TCGA) 数据库中的 AXL 相关基因表达来研究 AXL 信号通路。分别在 26.1% 和 53.3% 的治疗前EGFR突变 NSCLC 肿瘤中检测到高水平的 AXL 和阳性 p53 表达。与低 AXL 表达水平相比，高 AXL 表达水平与较短的无进展生存期显着相关，无论EGFR激活突变状态如何（p = 0.026）。基于细胞系的测定表明，AXL 蛋白的过表达加速了 PD-L1 的表达，从而导致对奥希替尼的不敏感性。在 TCGA 数据库中，AXL RNA 水平与肺腺癌队列中的 PD-L1 表达呈正相关。结果表明，当使用奥希替尼治疗EGFR突变的 NSCLC 患者时，肿瘤中的高 AXL 表达水平会影响临床预测。试用注册：UMIN000043942。