MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling
MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling
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DOI：
10.1126/science.1141478
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发表时间：
2007-05-18
期刊：
影响因子：
56.9
通讯作者：
Janne, Pasi A.
中科院分区：
文献类型：
--
作者：
Engelman, Jeffrey A.;Zejnullahu, Kreshnik;Janne, Pasi A.
表皮生长因子受体(EGFR)激酶抑制剂吉非替尼和厄洛替尼是治疗具有EGFR激活突变的肺癌的有效药物，但这些肿瘤总是产生耐药性。在这里，我们描述了一种对吉非替尼敏感的肺癌细胞株，由于MET原癌基因的局部扩增，该细胞株对吉非替尼产生了耐药性。抑制这些细胞中的MET信号，恢复了它们对吉非替尼的敏感性。18例对吉非替尼或厄洛替尼耐药的肺癌标本中有4例(22%)检测到MET扩增。我们发现，MET的扩增通过驱动依赖于ERBB3(HER3)的PI3K激活而导致吉非替尼耐药，PI3K被认为是EGFR/ERBB家族受体的特异性途径。因此，我们认为MET扩增可能也会促进其他ERBB驱动的癌症的耐药性。
The epidermal growth factor receptor (EGFR) kinase inhibitors gefitinib and erlotinib are effective treatments for lung cancers with EGFR activating mutations, but these tumors invariably develop drug resistance. Here, we describe a gefitinib-sensitive lung cancer cell line that developed resistance to gefitinib as a result of focal amplification of the MET proto-oncogene. inhibition of MET signaling in these cells restored their sensitivity to gefitinib. MET amplification was detected in 4 of 18 (22%) lung cancer specimens that had developed resistance to gefitinib or erlotinib. We find that amplification of MET causes gefitinib resistance by driving ERBB3 (HER3)-dependent activation of PI3K, a pathway thought to be specific to EGFR/ERBB family receptors. Thus, we propose that MET amplification may promote drug resistance in other ERBB-driven cancers as well.