Tokumo Masaki, Toyooka Shinichi, Ichihara Shuji, Ohashi Kadoaki, Tsukuda Kazunori, Ichimura Kouichi, Tabata Masahiro, Kiura Katsuyuki, Aoe Motoi, Sano Yoshifumi, Date Hiroshi, Shimizu Nobuyoshi
Department of Cancer and Thoracic Surgery, Graduate School of Medicine and Dentistry, Okayama University, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Lung Cancer. 2006 Jul;53(1):117-21. doi: 10.1016/j.lungcan.2006.04.008. Epub 2006 May 30.
Mutations of the epidermal growth factor receptor (EGFR) gene have been reported in non-small-cell lung cancer (NSCLC), especially in patients with adenocarcinoma and never smokers. Some common somatic mutations in EGFR, including deletion mutations in exon 19 and leucine-to-arginine substitution at amino acid position 858 (L858R) in exon 21, have been examined for their ability to predict sensitivity to gefitinib or erlotinib, which are selective EGFR tyrosine kinase inhibitors (EGFR-TKIs). On the other hand, reports have shown that the threonine-to-methionine substitution at amino acid position 790 (T790M) in exon 20 is related to gefitinib resistance. Some studies have indicated that high copy numbers of the EGFR gene may be a more effective molecular predictor to responsiveness and prolonged survival in patients treated with EGFR-TKIs. Here, we describe two NSCLC patients with the L858R mutation who did not respond to gefitinib. Case 1 harbored both the T790M and L858R mutations, and fluorescence in situ hybridization showed EGFR gene amplification. Case 2 harbored both the L858R and aspartic acid-to-tyrosine substitution at amino acid position 761 in exon 19 of EGFR mutations and had a high polysomy status for EGFR. In these two cases, tumors showed resistance to gefitinib treatment despite the presence of EGFR L858R mutation and increased copy number. Our findings encourage further molecular analysis to elucidate the relationship between the EGFR status, including mutations and amplifications, and the responsiveness of NSCLC to gefitinib.
表皮生长因子受体（EGFR）基因的突变已在非小细胞肺癌（NSCLC）中被报道，尤其是在腺癌患者和从不吸烟者中。EGFR中的一些常见体细胞突变，包括外显子19的缺失突变和外显子21中第858位氨基酸（L858R）的亮氨酸到精氨酸替代，已被检测其预测对吉非替尼或厄洛替尼敏感性的能力，这两种药物是选择性EGFR酪氨酸激酶抑制剂（EGFR-TKIs）。另一方面，报告显示外显子20中第790位氨基酸（T790M）的苏氨酸到蛋氨酸替代与吉非替尼耐药有关。一些研究表明，EGFR基因的高拷贝数可能是接受EGFR-TKIs治疗患者反应性和延长生存期更有效的分子预测指标。在此，我们描述了两名携带L858R突变但对吉非替尼无反应的NSCLC患者。病例1同时携带T790M和L858R突变，荧光原位杂交显示EGFR基因扩增。病例2同时携带L858R和EGFR外显子19中第761位氨基酸的天冬氨酸到酪氨酸替代突变，且EGFR具有高多体状态。在这两个病例中，尽管存在EGFR L858R突变和拷贝数增加，但肿瘤对吉非替尼治疗仍显示耐药。我们的发现鼓励进一步进行分子分析，以阐明EGFR状态（包括突变和扩增）与NSCLC对吉非替尼反应性之间的关系。
