Kwak Eunice L, Sordella Raffaella, Bell Daphne W, Godin-Heymann Nadia, Okimoto Ross A, Brannigan Brian W, Harris Patricia L, Driscoll David R, Fidias Panos, Lynch Thomas J, Rabindran Sridhar K, McGinnis John P, Wissner Allan, Sharma Sreenath V, Isselbacher Kurt J, Settleman Jeffrey, Haber Daniel A
Center for Molecular Therapeutics, Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
Proc Natl Acad Sci U S A. 2005 May 24;102(21):7665-70. doi: 10.1073/pnas.0502860102. Epub 2005 May 16.
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.
在表皮生长因子受体（EGFR）激酶结构域发生激活突变的非小细胞肺癌（NSCLC）对可逆性酪氨酸激酶抑制剂吉非替尼（易瑞沙）和厄洛替尼（特罗凯）表现出显著但短暂的反应。一些复发性肿瘤在EGFR激酶结构域有常见的继发性突变T790M，从而导致耐药，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。为了确定对吉非替尼获得性耐药的其他机制，我们使用携带激活型EGFR突变的NSCLC细胞在体外产生多个耐药克隆。这些耐药细胞在其生存能力方面表现出对EGFR和ERBB2信号传导的持续依赖性，并且未获得继发性EGFR突变。然而，它们显示出配体激活的EGFR内化增加，这与受体转运改变一致。尽管吉非替尼耐药克隆对相关的苯胺喹唑啉类药物具有交叉耐药性，但它们对一类EGFR不可逆抑制剂表现出敏感性。这些抑制剂还显示出对T790M突变型EGFR信号传导的有效抑制以及对具有T790M突变的NSCLC细胞的杀伤作用。因此，不可逆酪氨酸激酶抑制剂可规避吉非替尼的两种耐药机制。我们的研究结果表明，其中一种抑制剂HKI-272可能在治疗EGFR突变的NSCLC中证明非常有效，包括对吉非替尼或厄洛替尼已产生耐药性的肿瘤。
