Analysis of epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer and acquired resistance to gefitinib
Analysis of epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer and acquired resistance to gefitinib
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DOI：
10.1158/1078-0432.ccr-06-0714
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发表时间：
2006-10-01
影响因子：
11.5
通讯作者：
Mitsudomi, Tetsuya
中科院分区：
文献类型：
--
作者：
Kosaka, Takayuki;Yatabe, Yasushi;Mitsudomi, Tetsuya
目的：携带表皮生长因子受体 (EGFR) 基因激活突变的非小细胞肺癌对 EGFR 特异性酪氨酸激酶抑制剂高度敏感。然而，大多数最初有反应的患者随后在接受治疗时会出现疾病进展。这种“获得性耐药”的部分原因可归因于二次突变，导致 EGFR 密码子 790 (T790M) 处的苏氨酸变为甲硫氨酸。 实验设计：我们对 EGFR 基因的外显子 18 至 21 进行了测序，以寻找 14 名腺癌患者对吉非替尼获得性耐药的肿瘤中的二次突变。除了正常测序之外，还使用亚克隆或循环 PCR 来提高测定的灵敏度。我们还在 52 名接受吉非替尼治疗的患者的治疗前样本中寻找 T790M。我们还寻找继发性 KRAS 基因突变，因为具有 KRAS 突变的肿瘤通常对酪氨酸激酶抑制剂具有耐药性。结果：14 个肿瘤中有 7 个具有继发性 T790M 突变。没有其他新的二次突变。我们在这七个肿瘤中可用的五个肿瘤的治疗前标本中未检测到 T790M 突变。 T790M 患者往往是女性、从不吸烟且携带缺失突变，但 T790M 与吉非替尼给药持续时间无关。所有肿瘤均未出现 KRAS 基因获得性突变。结论：日本患者对吉非替尼获得性耐药的肿瘤中，一半存在 EGFR 继发性 T790M 突变。其他耐药二次突变在 EGFR 基因中并不常见。
Purpose: Non-small cell lung cancers carrying activating mutations in the gene for the epidermal growth factor receptor (EGFR) are highly sensitive to EGFR-specific tyrosine kinase inhibitors. However, most patients who initially respond subsequently experience disease progression while still on treatment. Part of this "acquired resistance" is attributable to a secondary mutation resulting in threonine to methionine at codon 790 (T790M) of EGFR.Experimental Design: We sequenced exons 18 to 21 of the EGFR gene to look for secondary mutations in tumors with acquired resistance to gefitinib in 14 patients with adenocarcinomas. Subcloning or cycleave PCR was used in addition to normal sequencing to increase the sensitivity of the assay. We also looked for T790M in pretreatment samples from 52 patients who were treated with gefitinib. We also looked for secondary KRAS gene mutations because tumors with KRAS mutations are generally resistant to tyrosine kinase inhibitors.Results: Seven of 14 tumors had a secondary T790M mutation. There were no other novel secondary mutations. We detected no T790M mutations in pretreatment specimens from available five tumors among these seven tumors. Patients with T790M tended to be women, never smokers, and carrying deletion mutations, but the T790M was not associated with the duration of gefitinib administration. None of the tumors had an acquired mutation in the KRAS gene.Conclusions: A secondary T790M mutation of EGFR accounted for half the tumors with acquired resistance to gefitinib in Japanese patients. Other drug-resistant secondary mutations are uncommon in the EGFR gene.