EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors.
EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors.
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DOI：
10.1158/1078-0432.ccr-14-2789
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发表时间：
2015-09-01
期刊：
影响因子：
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通讯作者：
Jänne PA
中科院分区：
文献类型：
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作者：
Ercan D;Choi HG;Yun CH;Capelletti M;Xie T;Eck MJ;Gray NS;Jänne PA
突变选择性不可逆嘧啶类EGFR激酶抑制剂，包括WZ 4002、CO-1686和AZD 9291，在临床前模型和携带EGFR T790 M吉非替尼/厄洛替尼耐药突变的肺癌患者中有效。然而，关于癌症如何对这类EGFR抑制剂产生获得性耐药性知之甚少。我们试图确定和研究EGFR突变，赋予耐药这类药物。我们在EGFR突变体（单独或与EGFR T790 M同时致敏）Ba/F3细胞和选定的耐药克隆中进行了N-乙基-N-亚硝基脲（ENU）诱变筛选。我们评估了EGFR抑制剂在携带耐药EGFR突变的模型中的敏感性。我们发现了3种主要的耐药突变。EGFR L718 Q、L 844 V和C797 S导致对WZ 4002和CO-1686的耐药性，而相比之下，仅EGFR C797 S导致AZD 9291耐药性。含有EGFR致敏突变Del 19或L 858 R以及L718 Q、L 844 V或C797 S的细胞保留对基于喹唑啉的EGFR抑制剂吉非替尼和阿法替尼的敏感性。在Del 19或L 858 R和T790 M存在下，C797 S突变导致对所有当前EGFR抑制剂的抗性，但L 858 R/T790 M/C797 S仍然对西妥昔单抗部分敏感，这导致EGFR二聚化的破坏。我们的研究结果提供了对基于不可逆嘧啶的EGFR抑制剂的耐药机制的见解，并确定了对现有临床EGFR抑制剂保持敏感性的特定基因组背景。这些发现将指导抑制EGFR的新策略的开发。
Mutant selective irreversible pyrimidine based EGFR kinase inhibitors, including WZ4002, CO-1686 and AZD9291, are effective in preclinical models and in lung cancer patients harboring the EGFR T790M gefitinib/erlotinib resistance mutation. However, little is known about how cancers develop acquired resistance to this class of EGFR inhibitors. We sought to identify and study EGFR mutations that confer resistance to this class of agents. We performed an N-ethyl-N-nitrosourea (ENU) mutagenesis screen in EGFR mutant (sensitizing alone or with concurrent EGFR T790M) Ba/F3 cells and selected drug resistant clones. We evaluated the sensitivity of EGFR inhibitors in models harboring drug resistant EGFR mutations. We identified 3 major drug resistance mutations. EGFR L718Q, L844V and C797S cause resistance to both WZ4002 and CO-1686 while, in contrast, only EGFR C797S leads to AZD9291 resistance. Cells containing an EGFR sensitizing mutation, Del 19 or L858R, in conjunction with L718Q, L844V or C797S retain sensitivity to quinazoline based EGFR inhibitors gefitinib and afatinib. The C797S mutation, in the presence of Del 19 or L858R and T790M, causes resistance to all current EGFR inhibitors, but L858R/T790M/C797S remains partially sensitive to cetuximab which leads to disruption of EGFR dimerization. Our findings provide insights into resistance mechanisms to irreversible pyrimidine based EGFR inhibitors and identify specific genomic contexts in which sensitivity is retained to existing clinical EGFR inhibitors. These findings will guide the development of new strategies to inhibit EGFR.