摘要

Lung adenocarcinomas from patients who respond to the tyrosine kinase inhibitors gefitinib (Iressa) or erlotinib (Tarceva) usually harbor somatic gain-of-function mutations in exons encoding the kinase domain of the epidermal growth factor receptor (EGFR). Despite initial responses, patients eventually progress by unknown mechanisms of "acquired" resistance.We show that in two of five patients with acquired resistance to gefitinib or erlotinib, progressing tumors contain, in addition to a primary drug-sensitive mutation in EGFR, a secondary mutation in exon 20, which leads to substitution of methionine for threonine at position 790 (T790M) in the kinase domain. Tumor cells from a sixth patient with a drug-sensitive EGFR mutation whose tumor progressed on adjuvant gefitinib after complete resection also contained the T790M mutation. This mutation was not detected in untreated tumor samples. Moreover, no tumors with acquired resistance had KRAS mutations, which have been associated with primary resistance to these drugs. Biochemical analyses of transfected cells and growth inhibition studies with lung cancer cell lines demonstrate that the T790M mutation confers resistance to EGFR mutants usually sensitive to either gefitinib or erlotinib. Interestingly, a mutation analogous to T790M has been observed in other kinases with acquired resistance to another kinase inhibitor, imatinib (Gleevec).In patients with tumors bearing gefitinib- or erlotinib-sensitive EGFR mutations, resistant subclones containing an additional EGFR mutation emerge in the presence of drug. This observation should help guide the search for more effective therapy against a specific subset of lung cancers.

译文

来自对酪氨酸激酶抑制剂吉非替尼 (易瑞沙) 或厄洛替尼 (特罗凯) 有反应的患者的肺癌通常在表皮生长因子受体 (EGFR) 的激酶结构域编码的 exons 中携带体细胞获得功能突变。尽管最初有反应,患者最终还是通过未知的 “获得性” 抵抗机制进展。我们表明,在对吉非替尼或厄洛替尼获得性耐药的五名患者中的两名中,除了 EGFR 的一种原发性药物敏感突变外,进展中的肿瘤还包含 20 号 exon 的一种继发性突变,这导致在激酶结构域的 790 位 (T790M) 将蛋氨酸替换为苏氨酸。来自第六例具有药物敏感 EGFR 突变的患者的肿瘤细胞,其肿瘤在完全切除后在吉非替尼辅助治疗下进展,也包含 T790M 突变。未经处理的肿瘤样本中未检测到这种突变。此外,没有获得性耐药的肿瘤有 KRAS 突变,这与对这些药物的原发性耐药有关。对转染细胞的生化分析和对肺癌细胞系的生长抑制研究表明,T790M 突变对通常对吉非替尼或厄洛替尼敏感的 EGFR 突变体具有耐药性。有趣的是,在对另一种激酶抑制剂伊马替尼 (Gleevec) 具有获得性抗性的其他激酶中观察到类似 T790M 的突变。在携带吉非替尼或厄洛替尼敏感 EGFR 突变的肿瘤患者中,含有额外 EGFR 突变的耐药亚克隆在药物存在的情况下出现。这一观察将有助于指导寻找针对特定肺癌子集的更有效的治疗方法。

Erlotinib

肿瘤 肺癌 药物
概述  :  

厄洛替尼是一个酪氨酸激酶抑制剂(TKI),可逆性的抑制特定类型的EGFR突变。EGFR(表皮生长因子受体)存在于人体正常细胞和癌细胞表面,与细胞的生长及复制息息相关。吉非替尼抑制EGFR,可以阻断依赖EGFR的细胞的增殖,达到抑制肿瘤细胞生长的目的。2013年5月14日,美国食品药品监督管理局(FDA)批准了厄洛替尼(Tarceva®,安斯泰来制药公司)用于一线治疗转移性非小细胞肺癌(NSCLC)。这些转移性NSCLC患者的一个重要特征是肿瘤组织的EGFR第19个外显子存在缺失突变或第21个

Erlotinib

释    义   n. 埃罗替尼;厄洛替尼;特罗凯

例    句   By inhibition of phosphorylation of tyrosine kinase, erlotinib blocks the EGFR tyrosine kinase protein in the cancer cell from getting a message that tells the cell to grow and divide. 盐酸埃罗替尼是一种小分子表皮生长因子酪氨酸激酶可逆抑制剂,通过抑制酪氨酸激酶的磷酸化,阻断信号传导,抑制肿瘤生长。

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