Pao William, Miller Vincent, Zakowski Maureen, Doherty Jennifer, Politi Katerina, Sarkaria Inderpal, Singh Bhuvanesh, Heelan Robert, Rusch Valerie, Fulton Lucinda, Mardis Elaine, Kupfer Doris, Wilson Richard, Kris Mark, Varmus Harold
Program in Cancer Biology and Genetics and Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13306-11. doi: 10.1073/pnas.0405220101. Epub 2004 Aug 25.
Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene are reportedly associated with sensitivity of lung cancers to gefitinib (Iressa), kinase inhibitor. In-frame deletions occur in exon 19, whereas point mutations occur frequently in codon 858 (exon 21). We found from sequencing the EGFR TK domain that 7 of 10 gefitinib-sensitive tumors had similar types of alterations; no mutations were found in eight gefitinib-refractory tumors (P = 0.004). Five of seven tumors sensitive to erlotinib (Tarceva), a related kinase inhibitor for which the clinically relevant target is undocumented, had analogous somatic mutations, as opposed to none of 10 erlotinib-refractory tumors (P = 0.003). Because most mutation-positive tumors were adenocarcinomas from patients who smoked <100 cigarettes in a lifetime ("never smokers"), we screened EGFR exons 2-28 in 15 adenocarcinomas resected from untreated never smokers. Seven tumors had TK domain mutations, in contrast to 4 of 81 non-small cell lung cancers resected from untreated former or current smokers (P = 0.0001). Immunoblotting of lysates from cells transiently transfected with various EGFR constructs demonstrated that, compared to wild-type protein, an exon 19 deletion mutant induced diminished levels of phosphotyrosine, whereas the phosphorylation at tyrosine 1092 of an exon 21 point mutant was inhibited at 10-fold lower concentrations of drug. Collectively, these data show that adenocarcinomas from never smokers comprise a distinct subset of lung cancers, frequently containing mutations within the TK domain of EGFR that are associated with gefitinib and erlotinib sensitivity.
据报道，表皮生长因子受体（EGFR）基因酪氨酸激酶（TK）结构域中的体细胞突变与肺癌对吉非替尼（易瑞沙）（一种激酶抑制剂）的敏感性相关。19外显子发生框内缺失，而点突变常见于密码子858（21外显子）。我们通过对EGFR TK结构域进行测序发现，10个对吉非替尼敏感的肿瘤中有7个具有相似类型的改变；在8个对吉非替尼耐药的肿瘤中未发现突变（P = 0.004）。7个对厄洛替尼（特罗凯）敏感的肿瘤中有5个具有类似的体细胞突变，厄洛替尼是一种相关激酶抑制剂，其临床相关靶点尚未明确，而10个对厄洛替尼耐药的肿瘤中无一例有此类突变（P = 0.003）。由于大多数突变阳性肿瘤是来自终生吸烟少于100支的患者（“从不吸烟者”）的腺癌，我们对15例从未接受过治疗的从不吸烟者切除的腺癌进行了EGFR第2至28外显子的筛查。7个肿瘤有TK结构域突变，相比之下，从未接受过治疗的既往或当前吸烟者切除的81例非小细胞肺癌中有4例有突变（P = 0.0001）。对用各种EGFR构建体瞬时转染的细胞裂解物进行免疫印迹分析表明，与野生型蛋白相比，19外显子缺失突变体诱导的磷酸酪氨酸水平降低，而21外显子点突变体酪氨酸1092位点的磷酸化在药物浓度低10倍时受到抑制。总体而言，这些数据表明，从不吸烟者的腺癌构成肺癌的一个独特亚组，经常含有EGFR TK结构域内与吉非替尼和厄洛替尼敏感性相关的突变。
