Semaphorin 7A promotes EGFR-TKI resistance in EGFR mutant lung adenocarcinoma cells
Semaphorin 7A promotes EGFR-TKI resistance in EGFR mutant lung adenocarcinoma cells
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DOI：
10.1172/jci.insight.123093
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发表时间：
2018-12-20
期刊：
影响因子：
8
通讯作者：
Kumanogoh, Atsushi
中科院分区：
文献类型：
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作者：
Kinehara, Yuhei;Nagatomo, Izumi;Kumanogoh, Atsushi
尽管对EGFR酪氨酸激酶抑制剂(EGFR-TKI)的反应最初是阳性的，但30%-40%的EGFR突变肿瘤患者对EGFR-TKI反应不佳，大多数携带EGFR突变的肺癌患者经历了复发和耐药。因此，不仅有必要确定EGFR-TKI耐药的机制，而且有必要确定EGFR突变的肺腺癌潜在的新的治疗靶点和/或预测生物标志物。我们发现，GPI锚定蛋白信号素7A(SEMA7A)是由EGFR途径通过mTOR信号通路高度诱导的，并且SEMA7A在人肺腺癌标本中的表达水平与mTOR激活有关。使用细胞培养和动物模型的研究表明，SEMA7A的缺失或过表达分别使细胞对EGFR-TKI的抵抗力降低或增强。耐药原因是ERK的异常激活抑制了细胞的凋亡。ERK信号被整合素β1(ITGB1)敲除后被抑制。此外，在EGFR突变肿瘤患者中，临床样本中SEMA7A的高表达预示着对EGFR-TKI治疗的较差反应。综上所述，这些数据表明，SEMA7A-ITGB1轴在ERK激活和细胞凋亡抑制介导的EGFR-TKI抵抗中起着关键作用。此外，我们的结果揭示了SEMA7A不仅作为预测生物标志物的潜在用途，而且作为EGFR突变的肺腺癌潜在的新的治疗靶点。
Although responses to EGFR tyrosine kinase inhibitors (EGFR-TKIs) are initially positive, 30%-40% of patients with EGFR-mutant tumors do not respond well to EGFR-TKIs, and most lung cancer patients harboring EGFR mutations experience relapse with resistance. Therefore, it is necessary to identify not only the mechanisms underlying EGFR-TKI resistance, but also potentially novel therapeutic targets and/or predictive biomarkers for EGFR-mutant lung adenocarcinoma. We found that the GPI-anchored protein semaphorin 7A (SEMA7A) is highly induced by the EGFR pathway, via mTOR signaling, and that expression levels of SEMA7A in human lung adenocarcinoma specimens were correlated with mTOR activation. Investigations using cell culture and animal models demonstrated that loss or overexpression of SEMA7A made cells less or more resistant to EGFR-TKIs, respectively. The resistance was due to the inhibition of apoptosis by aberrant activation of ERK. The ERK signal was suppressed by knockdown of integrin beta 1 (ITGB1). Furthermore, in patients with EGFR mutant tumors, higher SEMA7A expression in clinical samples predicted poorer response to EGFR-TKI treatment. Collectively, these data show that the SEMA7A-ITGB1 axis plays pivotal roles in EGFR-TKI resistance mediated by ERK activation and apoptosis inhibition. Moreover, our results reveal the potential utility of SEMA7A not only as a predictive biomarker, but also as a potentially novel therapeutic target in EGFR-mutant lung adenocarcinoma.