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首页> 外文期刊>EBioMedicine >Common Co-activation of AXL and CDCP1 in EGFR -mutation-positive Non-Small Cell Lung Cancer Associated With Poor Prognosis
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Common Co-activation of AXL and CDCP1 in EGFR -mutation-positive Non-Small Cell Lung Cancer Associated With Poor Prognosis

机译：与不良预后相关的EGFR突变阳性非小细胞肺癌中AXL和CDCP1的共同激活

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Epidermal growth factor receptor ( EGFR )-mutation-positive non-small cell lung cancer (NSCLC) is incurable, despite high rates of response to EGFR tyrosine kinase inhibitors (TKIs). We investigated receptor tyrosine kinases (RTKs), Src family kinases and focal adhesion kinase (FAK) as genetic modifiers of innate resistance in EGFR -mutation-positive NSCLC. We performed gene expression analysis in two cohorts (Cohort 1 and Cohort 2) of EGFR -mutation-positive NSCLC patients treated with EGFR TKI. We evaluated the efficacy of gefitinib or osimertinib with the Src/FAK/Janus kinase 2 (JAK2) inhibitor, TPX0005 in vitro and in vivo. In Cohort 1, CUB domain-containing protein-1 (CDCP1) was an independent negative prognostic factor for progression-free survival (hazard ratio of 1.79, p = 0.0407) and overall survival (hazard ratio of 2.23, p = 0.0192). A two-gene model based on AXL and CDCP1 expression was strongly associated with the clinical outcome to EGFR TKIs, in both cohorts of patients. Our preclinical experiments revealed that several RTKs and non-RTKs, were up-regulated at baseline or after treatment with gefitinib or osimertinib. TPX-0005 plus EGFR TKI suppressed expression and activation of RTKs and downstream signaling intermediates. Co-expression of CDCP1 and AXL is often observed in EGFR -mutation-positive tumors, limiting the efficacy of EGFR TKIs. Co-treatment with EGFR TKI and TPX-0005 warrants testing.
机译：尽管对EGFR酪氨酸激酶抑制剂（TKIs）的反应率很高，但表皮生长因子受体（EGFR）突变阳性的非小细胞肺癌（NSCLC）是无法治愈的。我们调查了受体酪氨酸激酶（RTKs），Src家族激酶和粘着斑激酶（FAK）作为EGFR突变阳性NSCLC中先天性耐药的遗传修饰因子。我们在接受EGFR TKI治疗的EGFR突变阳性NSCLC患者的两个队列（队列1和队列2）中进行了基因表达分析。我们在体外和体内评估了吉非替尼或奥西替尼与Src / FAK / Janus激酶2（JAK2）抑制剂TPX0005的疗效。在队列1中，含CUB域的蛋白1（CDCP1）是无进展生存期（危险比1.79，p = 0.0407）和总生存期（危险比2.22，p = 0.0192）的独立阴性预后因素。在两组患者中，基于AXL和CDCP1表达的双基因模型与EGFR TKIs的临床结局密切相关。我们的临床前实验表明，在基线时或吉非替尼或奥西替尼治疗后，几种RTK和非RTK均被上调。 TPX-0005加EGFR TKI抑制RTK和下游信号传导中间体的表达和激活。在EGFR突变阳性肿瘤中经常观察到CDCP1和AXL的共表达，从而限制了EGFR TKIs的疗效。与EGFR TKI和TPX-0005的共同治疗需要进行测试。

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