IGFBP7 Drives Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibition in Lung Cancer
IGFBP7 Drives Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibition in Lung Cancer
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DOI：
10.3390/cancers11010036
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发表时间：
2019-01-01
期刊：
影响因子：
5.2
通讯作者：
Shih, Jin-Yuan
中科院分区：
文献类型：
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作者：
Wu, Shang-Gin;Chang, Tzu-Hua;Shih, Jin-Yuan
表皮生长因子受体（EGFR）突变阳性肺癌患者对EGFR-酪氨酸激酶抑制剂（TKI）表现出显着的反应。然而，获得性耐药性最终会发展。本研究探讨了与TKI耐药相关的新机制。为了鉴定与TKI耐药相关的基因，使用综合方法分析公共数据集。采用分子生物学方法研究胰岛素样生长因子结合蛋白7（IGFBP 7）在肺腺癌中的作用。采集临床样本以验证IGFBP 7对EGFR TKI治疗疗效的影响。在对EGFR-TKI获得性耐药后从恶性胸腔积液分离的癌细胞中IGFBP 7 mRNA表达显著高于来自未经治疗的胸腔积液的癌细胞。与TKI敏感的亲本细胞相比，在具有长期TKI诱导的抗性的细胞中IGFBP 7表达显著增加。TKI耐药细胞中IGFBP 7的减少逆转了对EGFR-TKI的耐药性，并通过上调B细胞淋巴瘤2相互作用的细胞死亡介质（BIM）和激活半胱天冬酶来增加EGFR-TKI诱导的细胞凋亡。IGFBP 7的抑制减弱了TKI耐药细胞中胰岛素样生长因子1受体（IGF-IR）和下游蛋白激酶B（AKT）的磷酸化。临床上，较高的血清IGFBP 7水平和IGFBP 7免疫组化染色阳性的肿瘤与TKI治疗结果较差相关。IGFBP 7赋予对EGFR-TKI的抗性，并且是用于治疗EGFR-TKI抗性癌症的潜在治疗靶标。
Patients with epidermal growth factor receptor (EGFR) mutation-positive lung cancer show a dramatic response to EGFR-tyrosine kinase inhibitors (TKIs). However, acquired drug resistance eventually develops. This study explored the novel mechanisms related to TKI resistance. To identify the genes associated with TKI resistance, an integrative approach was used to analyze public datasets. Molecular manipulations were performed to investigate the roles of insulin-like growth factor binding protein 7 (IGFBP7) in lung adenocarcinoma. Clinical specimens were collected to validate the impact of IGFBP7 on the efficacy of EGFR TKI treatment. IGFBP7 mRNA expression in cancer cells isolated from malignant pleural effusions after acquired resistance to EGFR-TKI was significantly higher than in cancer cells from treatment-naive effusions. IGFBP7 expression was markedly increased in cells with long-term TKI-induced resistance compared to in TKI-sensitive parental cells. Reduced IGFBP7 in TKI-resistant cells reversed the resistance to EGFR-TKIs and increased EGFR-TKI-induced apoptosis by up-regulating B-cell lymphoma 2 interacting mediator of cell death (BIM) and activating caspases. Suppression of IGFBP7 attenuated the phosphorylation of insulin-like growth factor 1 receptor (IGF-IR) and downstream protein kinase B (AKT) in TKI-resistant cells. Clinically, higher serum IGFBP7 levels and tumors with positive IGFBP7-immunohistochemical staining were associated with poor TKI-treatment outcomes. IGFBP7 confers resistance to EGFR-TKIs and is a potential therapeutic target for treating EGFR-TKI-resistant cancers.