Kosaka Takayuki, Yatabe Yasushi, Endoh Hideki, Yoshida Kimihide, Hida Toyoaki, Tsuboi Masahiro, Tada Hirohito, Kuwano Hiroyuki, Mitsudomi Tetsuya
Department of Thoracic Surgery, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.
Clin Cancer Res. 2006 Oct 1;12(19):5764-9. doi: 10.1158/1078-0432.CCR-06-0714.
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.
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.
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.
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.
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在仍接受治疗时随后会出现疾病进展。这种“获得性耐药”的部分原因是EGFR第790密码子（T790M）处发生苏氨酸到甲硫氨酸的继发性突变。
我们对14例腺癌患者中对吉非替尼产生获得性耐药的肿瘤的EGFR基因第18至21外显子进行测序，以寻找继发性突变。除常规测序外，还使用亚克隆或循环介导的PCR来提高检测的敏感性。我们还在52例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KRAS基因的继发性突变，因为具有KRAS突变的肿瘤通常对酪氨酸激酶抑制剂耐药。
14个肿瘤中有7个发生了继发性T790M突变。没有其他新的继发性突变。在这7个肿瘤中，我们在可获得的5个肿瘤的治疗前标本中未检测到T790M突变。携带T790M的患者倾向于是女性、从不吸烟者且携带缺失突变，但T790M与吉非替尼给药持续时间无关。所有肿瘤均未发生KRAS基因的获得性突变。
EGFR的继发性T790M突变在日本患者中占对吉非替尼产生获得性耐药的肿瘤的一半。EGFR基因中其他耐药性继发性突变并不常见。
