Weill Cornell Graduate School of Medical Sciences, New York, New York, USA.
J Thorac Oncol. 2012 Feb;7(2):434-42. doi: 10.1097/JTO.0b013e31823c5aee.
EGFR-mutant lung cancers are sensitive to EGFR tyrosine kinase inhibitors (TKIs). Unfortunately, they develop resistance, often due to acquisition of a second-site mutation (T790M). Current EGFR TKIs select for T790M in preclinical models of acquired resistance. We explored whether all EGFR TKIs similarly select for the T790M mutation using data from early clinical trials and established in vitro models of acquired resistance.
We analyzed the clinical characteristics of eight patients with metastatic EGFR-mutant lung adenocarcinoma who were treated first-line with XL647 and then progressed. XL647 is an ATP-competitive inhibitor of EGFR, HER2, KDR, and EPHB4. Additional molecular preclinical studies were performed to characterize resistance.
Four patients displayed confirmed partial responses (PRs), three patients had unconfirmed PRs, and one patient displayed stable disease. Only one of five patients' tumor samples available for analysis after disease progression harbored the T790M mutation. Eight patients subsequently received erlotinib, with (n = 3) or without (n = 5) chemotherapy. Three of five patients treated with single-agent erlotinib derived additional benefit, staying on drug up to 9 months. EGFR-mutant PC-9 cells with acquired resistance to XL647 did not harbor the T790M mutation, displayed a distinct mRNA profile from PC-9 cells with T790M-mediated resistance, and were moderately sensitive to erlotinib in growth inhibition assays. Crystal structure analyses of XL647/EGFR T790M did not reveal a different binding mode from that of erlotinib.
The findings of this exploratory study suggest that different EGFR TKIs may select for distinct mechanisms of resistance. These results raise the possibility that different EGFR TKIs could be sequentially used to improve outcomes in patients with EGFR-mutant lung cancer. Further work investigating this hypothesis is warranted.
表皮生长因子受体（EGFR）突变型肺癌对 EGFR 酪氨酸激酶抑制剂（TKI）敏感。不幸的是，它们会产生耐药性，通常是由于获得第二个点突变（T790M）。目前的 EGFR TKI 在获得性耐药的临床前模型中选择 T790M。我们通过对接受一线 XL647 治疗后进展的 8 例转移性 EGFR 突变型肺腺癌患者的早期临床试验和体外获得性耐药模型的数据进行分析，来探讨所有 EGFR TKI 是否同样选择 T790M 突变。
我们分析了 8 例接受 XL647 一线治疗后进展的转移性 EGFR 突变型肺腺癌患者的临床特征。XL647 是一种 ATP 竞争性的 EGFR、HER2、KDR 和 EPHB4 抑制剂。我们进行了额外的分子临床前研究来描述耐药性。
4 例患者出现确认的部分缓解（PR），3 例患者出现未确认的 PR，1 例患者出现疾病稳定。只有 1 例 5 例可供分析的疾病进展后肿瘤样本携带 T790M 突变。8 例患者随后接受了厄洛替尼治疗，其中 3 例联合化疗，5 例不联合化疗。5 例接受单药厄洛替尼治疗的患者中有 3 例获得额外的获益，最长用药时间达 9 个月。对 XL647 获得性耐药的 PC-9 细胞不携带 T790M 突变，其 mRNA 谱与 T790M 介导的耐药性 PC-9 细胞明显不同，在生长抑制试验中对厄洛替尼中度敏感。XL647/EGFR T790M 的晶体结构分析未显示出与厄洛替尼不同的结合模式。
这项探索性研究的结果表明，不同的 EGFR TKI 可能选择不同的耐药机制。这些结果提示不同的 EGFR TKI 可以序贯使用以改善 EGFR 突变型肺癌患者的结局。需要进一步研究来验证这一假说。
