MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib
MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib
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DOI：
10.1073/pnas.0710370104
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发表时间：
2007-12-26
影响因子：
11.1
通讯作者：
Pao, William
中科院分区：
文献类型：
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作者：
Bean, James;Brennan, Cameron;Pao, William
在携带EGFR突变的人肺腺癌中，第790位用蛋氨酸取代苏氨酸的第二位点突变(T790M)与大约一半的对EGFR激酶抑制剂吉非替尼和埃洛替尼的获得性耐药有关。为了确定导致疾病进展的其他潜在机制，我们使用基于阵列的比较基因组杂交(ACGH)来比较来自未经治疗的患者和获得性耐药患者的EGFR突变肿瘤的基因组图谱。在3个显示获得性耐药组特异性重复拷贝数改变(CNA)的基因座中，1个含有MET原癌基因。总体而言，对多个独立患者队列的肿瘤样本分析显示，43例获得性耐药患者中有9例(21%)MET在肿瘤中扩增，而62例未经治疗的患者中仅有2例(3%)MET基因扩增(P=0.007，Fisher‘s精确检验)。在9例MET扩增患者的10例耐药肿瘤中，4例同时携带EGFR(T790M)突变。我们还发现，现有的EGFR突变肺腺癌细胞株NCI-H820，除了对药物敏感的EGFR突变和T790M改变外，还存在MET扩增。生长抑制研究表明，这些细胞对厄洛替尼和不可逆的EGFR抑制剂(CL-387,785)都有耐药性，但对具有较强抗MET活性的多激酶抑制剂(XL880)敏感。综上所述，这些数据表明MET扩增独立于EGFR(T790M)突变发生，MET可能是一些对吉非替尼或厄洛替尼获得性耐药患者的临床相关治疗靶点。
in human lung adenocarcinomas harboring EGFR mutations, a second-site point mutation that substitutes methionine for threonine at position 790 (T790M) is associated with approximately half of cases of acquired resistance to the EGFR kinase inhibitors, gefitinib and erlotinib. To identify other potential mechanisms that contribute to disease progression, we used array-based comparative genomic hybridization (aCGH) to compare genomic profiles of EGFR mutant tumors from untreated patients with those from patients with acquired resistance. Among three loci demonstrating recurrent copy number alterations (CNAs) specific to the acquired resistance set, one contained the MET proto-oncogene. Collectively, analysis of tumor samples from multiple independent patient cohorts revealed that MET was amplified in tumors from 9 of 43 (21 %) patients with acquired resistance but in only two tumors from 62 untreated patients (3%) (P = 0.007, Fisher's Exact test). Among 10 resistant tumors from the nine patients with MET amplification, 4 also harbored the EGFR(T790M) mutation. We also found that an existing EGFR mutant lung adenocarcinoma cell line, NCI-H820, harbors MET amplification in addition to a drug-sensitive EGFR mutation and the T790M change. Growth inhibition studies demonstrate that these cells are resistant to both erlotinib and an irreversible EGFR inhibitor (CL-387,785) but sensitive to a multikinase inhibitor (XL880) with potent activity against MET. Taken together, these data suggest that MET amplification occurs independently of EGFR(T790M) mutations and that MET may be a clinically relevant therapeutic target for some patients with acquired resistance to gefitinib or erlotinib.