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首页> 外文期刊>EBioMedicine >Integrin-linked kinase (ILK) and src homology 2 domain-containing phosphatase 2 (SHP2): Novel targets in EGFR-mutation positive non-small cell lung cancer (NSCLC)
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Integrin-linked kinase (ILK) and src homology 2 domain-containing phosphatase 2 (SHP2): Novel targets in EGFR-mutation positive non-small cell lung cancer (NSCLC)

机译：整联蛋白连锁激酶（ILK）和src同源2域含磷酸酶2（SHP2）：EGFR突变阳性非小细胞肺癌（NSCLC）的新目标

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Background The activation of multiple signaling pathways jeopardizes the clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutation positive non-small cell lung cancer (NSCLC). Integrin-linked kinase (ILK) regulates the interactions between tumor cells and extracellular environment to activate signaling pathways and promote cell proliferation, migration, and epithelial-mesenchymal transition. Src homology 2 domain-containing phosphatase 2 (SHP2) is essential for receptor tyrosine kinase signaling and mitogen-activated protein kinase (MAPK) pathway activation. Methods We analyzed tumor ILK, β-receptor subunit glycoprotein 130 (gp130), SHP2, and stromal hepatocyte growth factor (HGF) and interleukin-6 (IL-6) mRNA expression in baseline tumor specimens of advanced EGFR-mutation positive NSCLC patients treated with EGFR TKIs. Results ILK, when highly expressed, was an independent poor prognostic factor for the progression-free survival of the patients, both in the univariate (hazard ratio [HR for disease progression, 2.49; 95% CI, 1.37–4.52; P ?=?.0020]) and in the multivariate (HR 3.74; 95% CI, 1.33–10.56; P ?=?.0126) Cox regression model. Patients with high SHP2 expression had an almost 13-month shorter progression-free survival ( P ?=?.0094) and an 18-month shorter overall survival ( P ?=?.0182) in comparison to those with low SHP2 mRNA expression. Interpretation The levels of ILK and SHP2 could be predictive for upfront combinatory therapy of EGFR TKIs plus SHP2 or ILK inhibitors. Fund A grant from La Caixa Foundation, an Instituto de Salud Carlos III grant (RESPONSE, PIE16/00011), an Instituto de Salud Carlos III grant (PI14/01678), a Marie Sk?odowska-Curie Innovative Training Networks European Grant (ELBA No 765492) and a Spanish Association Against Cancer (AECC) grant (PROYE18012ROSE).
机译：背景技术多种信号通路的激活会损害EGFR酪氨酸激酶抑制剂（TKIs）在EGFR突变阳性非小细胞肺癌（NSCLC）中的临床疗效。整联蛋白连接激酶（ILK）调节肿瘤细胞与细胞外环境之间的相互作用，以激活信号传导途径并促进细胞增殖，迁移和上皮-间质转化。包含Src同源2域的磷酸酶2（SHP2）对于受体酪氨酸激酶信号传导和丝裂原活化蛋白激酶（MAPK）途径活化至关重要。方法我们分析了晚期EGFR突变阳性NSCLC患者基线肿瘤标本中的肿瘤ILK，β受体亚基糖蛋白130（gp130），SHP2和基质肝细胞生长因子（HGF）和白细胞介素6（IL-6）mRNA的表达。 EGFR TKIs。结果ILK高表达时，是单变量患者无进展生存的独立不良预后因素（危险比[疾病进展的HR，2.49; 95％CI，1.37–4.52; P =？ [0020]）和多元分析（HR 3.74; 95％CI，1.33-10.56; P？= ?. 0126）Cox回归模型。与SHP2 mRNA低表达的患者相比，SHP2高表达的患者的无进展生存期缩短了近13个月（P =≤0.009），总生存期缩短了18个月（P≤≤.0182）。解释ILK和SHP2的水平可预示EGFR TKI加SHP2或ILK抑制剂的联合治疗。基金来自La Caixa基金会，萨洛德·卡洛斯三世研究所（RESPONSE，PIE16 / 00011），萨洛德·卡洛斯三世研究所（PI14 / 01678），玛丽·斯科多夫斯卡居里欧洲创新培训网络（ELBA）， 765492）和西班牙抗癌协会（AECC）资助（PROYE18012ROSE）。

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