Department of Thoracic Surgery, Aichi Cancer Center Hospital, 1-1 Kanokoden, Nagoya, Japan.
Clin Cancer Res. 2010 Nov 15;16(22):5489-98. doi: 10.1158/1078-0432.CCR-10-1371. Epub 2010 Nov 9.
In epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy for lung cancer patients, acquired resistance develops almost inevitably and this limits the improvement in patient outcomes. EGFR T790M mutation and MET amplification are the two main mechanisms underlying this resistance, but the relationship between these two mechanisms is unclear. In this study, we explored their relationship using in vitro models and autopsy specimens.
Erlotinib-resistant HCC827 (HCC827ER) cells were developed by chronic exposure to erlotinib at increasing concentrations. HCC827EPR cells were also developed by chronic exposure to erlotinib in the presence of PHA-665,752 (a MET TKI). The erlotinib-resistant mechanisms of these cells were analyzed. In addition, 33 autopsy tumor samples from 6 lung adenocarcinoma patients harboring multiple gefitinib-refractory tumors were analyzed.
HCC827ER developed MET amplification, and clinically relevant resistance occurred at ≥4-fold MET gene copy number gain (CNG). By contrast, HCC827EPR developed T790M without MET CNG. Of six patients harboring gefitinib-refractory tumors, three exhibited T790M only, one exhibited MET amplification only, and the other two exhibited T790M and/or MET amplification depending on the lesion sites. In these gefitinib-refractory tumors, T790M developed in 93% (14 of 15) of tumors without MET gene CNGs, in 80% (4 of 5) of tumors with moderate MET gene CNGs (<4-fold), and in only 8% (1 of 13) of tumors with MET amplification (≥4-fold).
These results indicate a reciprocal and complementary relationship between T790M and MET amplification and the necessity of concurrent inhibition of both for further improving patient outcomes.
在表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）治疗肺癌患者中，几乎不可避免地会出现获得性耐药，这限制了患者结局的改善。EGFR T790M 突变和 MET 扩增是导致这种耐药的两个主要机制，但这两种机制之间的关系尚不清楚。在这项研究中，我们使用体外模型和尸检标本探索了它们之间的关系。
通过在不断增加的浓度下用厄洛替尼慢性处理，开发出对厄洛替尼耐药的 HCC827（HCC827ER）细胞。还通过在厄洛替尼存在 PHA-665752（一种 MET TKI）的情况下用厄洛替尼慢性处理，开发出 HCC827EPR 细胞。分析这些细胞的厄洛替尼耐药机制。此外，分析了来自 6 名肺腺癌患者的 33 个尸检肿瘤样本，这些患者均存在多个吉非替尼耐药肿瘤。
HCC827ER 发生 MET 扩增，并且在≥4 倍 MET 基因拷贝数增加（CNG）时出现临床相关耐药。相比之下，HCC827EPR 仅发生 T790M 突变，而无 MET CNG。在携带吉非替尼耐药肿瘤的 6 名患者中，3 名患者仅发生 T790M，1 名患者仅发生 MET 扩增，而另外 2 名患者根据病变部位发生 T790M 和/或 MET 扩增。在这些吉非替尼耐药肿瘤中，在无 MET 基因 CNG 的肿瘤中 93%（14/15）发生 T790M，在中度 MET 基因 CNG（<4 倍）的肿瘤中 80%（4/5）发生 T790M，而在发生 MET 扩增（≥4 倍）的肿瘤中仅发生 8%（1/13）。
这些结果表明 T790M 和 MET 扩增之间存在相互和互补的关系，需要同时抑制两者以进一步改善患者结局。
