Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib
Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib
复制标题
DOI：
10.1073/pnas.0502860102
复制
发表时间：
2005-05-24
影响因子：
11.1
通讯作者：
Haber, DA
中科院分区：
文献类型：
--
作者：
Kwak, EL;Sordella, R;Haber, DA
表皮生长因子受体 (EGFR) 激酶结构域发生激活突变的非小细胞肺癌 (NSCLC) 对可逆酪氨酸激酶抑制剂吉非替尼 (易瑞沙) 和厄洛替尼 (特罗凯) 表现出显着但短暂的反应。一些复发性肿瘤在 EGFR 激酶结构域 T790M 中存在常见的二次突变，从而产生耐药性，但在其他情况下，获得性耐药的潜在机制尚不清楚。在研究复发性 NSCLC 的多个部位时，我们仅在一小部分肿瘤细胞中检测到 T790M。为了确定吉非替尼获得性耐药的其他机制，我们使用带有激活 EGFR 突变的 NSCLC 细胞在体外产生多个耐药克隆。这些耐药细胞表现出其生存能力持续依赖 EGFR 和 ERBB2 信号传导，并且尚未获得继发性 EGFR 突变。然而，它们表现出配体激活的 EGFR 内化增加，这与受体运输的改变一致。尽管吉非替尼耐药克隆与相关苯胺喹唑啉具有交叉耐药性，但它们表现出对一类不可逆 EGFR 抑制剂的敏感性。这些抑制剂还可以有效抑制 T790M 突变 EGFR 的信号传导，并杀死具有 T790M 突变的 NSCLC 细胞。因此，吉非替尼耐药的两种机制都可以通过不可逆酪氨酸激酶抑制剂来规避。我们的研究结果表明，其中之一 HKI-272 可能在治疗 EGFR 突变非小细胞肺癌（包括对吉非替尼或厄洛替尼产生耐药性的肿瘤）方面非常有效。
Non-small cell lung cancers (NSCLCs) with activating mutations in the kinase domain of the epidermal growth factor receptor (EGFR) demonstrate dramatic, but transient, responses to the reversible tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva). Some recurrent tumors have a common secondary mutation in the EGFR kinase domain, T790M, conferring drug resistance, but in other cases the mechanism underlying acquired resistance is unknown. In studying multiple sites of recurrent NSCLCs, we detected T790M in only a small percentage of tumor cells. To identify additional mechanisms of acquired resistance to gefitinib, we used NSCLC cells harboring an activating EGFR mutation to generate multiple resistant clones in vitro. These drug-resistant cells demonstrate continued dependence on EGFR and ERBB2 signaling for their viability and have not acquired secondary EGFR mutations. However, they display increased internalization of ligand-activated EGFR, consistent with altered receptor trafficking. Although gefitinib-resistant clones are cross-resistant to related anilinoquinazolines, they demonstrate sensitivity to a class of irreversible inhibitors of EGFR. These inhibitors also show effective inhibition of signaling by T790M-mutant EGFR and killing of NSCLC cells with the T790M mutation. Both mechanisms of gefitinib resistance are therefore circumvented by irreversible tyrosine kinase inhibitors. Our findings suggest that one of these, HKI-272, may prove highly effective in the treatment of EGFR-mutant NSCLCs, including tumors that have become resistant to gefitinib or erlotinib.