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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines
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ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines

机译：ErbB-3介导吉非替尼敏感的非小细胞肺癌细胞系中的磷酸肌醇3-激酶活性

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摘要

Therapies that target the EGF receptor (EGFR), such as gefitinib (IRESSA), are effective in a subset of patients with advanced non-small cell lung cancer (NSCLC). The differences in intracellular signaling networks between gefitinib-sensitive and -resistant NSCLCs remain poorly understood. In this study, we observe that gefitinib reduces phospho-Akt levels only in NSCLC cell lines in which it inhibits growth. To elucidate the mechanism underlying this observation, we compared immunoprecipitates of phosphoinositide 3-kinase (PI3K) between gefitinib-sensitive and -resistant NSCLC cell lines. We observe that PI3K associates with ErbB-3 exclusively in gefitinib-sensitive NSCLC cell lines. Gefitinib dissociates this complex, thereby linking EGFR inhibition to decreased Akt activity. In contrast, gefitinib-resistant cells do not use ErbB-3 to activate the PI3K/Akt pathway. In fact, abundant ErbB-3 expression is detected only in gefitinib-sensitive NSCLC cell lines. Two gefitinib-sensitive NSCLC cell lines with endogenous distinct activating EGFR mutations (L858R and Del747-749), frequently observed in NSCLC patients who respond to gefitinib, also use ErbB-3 to couple to PI3K. Down-regulation of ErbB-3 by means of short hairpin RNA leads to decreased phospho-Akt levels in the gefitinib-sensitive NSCLC cell lines, Calu-3 (WT EGFR) and H3255 (L858R EGFR), but has no effect on Akt activation in the gefitinib-resistant cell lines, A549 and H522. We conclude that ErbB-3 is used to couple EGFR to the PI3K/Akt pathway in gefitinib-sensitive NSCLC cell lines harboring WT and mutant EGFRs.
机译：靶向EGF受体（EGFR）的疗法，例如吉非替尼（IRESSA），对部分晚期非小细胞肺癌（NSCLC）患者有效。吉非替尼敏感和耐药的NSCLC之间的细胞内信号网络的差异仍然知之甚少。在这项研究中，我们观察到吉非替尼只能在抑制生长的NSCLC细胞系中降低磷酸化Akt水平。为了阐明该观察结果的机制，我们比较了吉非替尼敏感和耐药的NSCLC细胞系之间的磷酸肌醇3-激酶（PI3K）免疫沉淀。我们观察到PI3K仅在吉非替尼敏感的NSCLC细胞系中与ErbB-3缔合。吉非替尼使该复合物解离，从而将EGFR抑制与降低的Akt活性联系起来。相反，耐吉非替尼的细胞不使用ErbB-3激活PI3K / Akt途径。实际上，仅在对吉非替尼敏感的NSCLC细胞系中检测到大量的ErbB-3表达。在对吉非替尼有反应的NSCLC患者中经常观察到的两种具有内源性独特激活EGFR突变的吉非替尼敏感的NSCLC细胞系（L858R和Del747-749）也使用ErbB-3与PI3K偶联。 ErbB-3通过短发夹RNA的下调导致吉非替尼敏感的NSCLC细胞系，Calu-3（WT EGFR）和H3255（L858R EGFR）的磷酸化Akt水平降低，但对Akt激活没有影响在耐吉非替尼的细胞株A549和H522中。我们得出的结论是，ErbB-3被用于将EGFR偶联到包含WT和突变EGFR的吉非替尼敏感的NSCLC细胞系中的PI3K / Akt途径。

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