Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors.
Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors.
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DOI：
10.1158/0008-5472.can-16-3404
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发表时间：
2017-05-15
期刊：
影响因子：
11.2
通讯作者：
Jänne PA
中科院分区：
文献类型：
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作者：
Kosaka T;Tanizaki J;Paranal RM;Endoh H;Lydon C;Capelletti M;Repellin CE;Choi J;Ogino A;Calles A;Ercan D;Redig AJ;Bahcall M;Oxnard GR;Eck MJ;Jänne PA
EGFR和HER 2中的插入突变均发生在外显子20中的类似位置。携带这些突变的肿瘤的非小细胞肺癌（NSCLC）患者很少对dacomitinib和afatinib（分别为两种基于喹唑啉的EGFR或HER 2共价抑制剂）达到临床缓解。在本研究中，我们研究了dacomitinib治疗后临床上达到部分缓解的NSCLC患者中特定EGFR和HER 2 20号外显子插入突变的影响。我们确定Gly 770是药物敏感突变的共同特征。结构建模表明，这种突变可能有助于抑制剂结合EGFR。将Gly 770引入两种dacomitinib耐药EGFR 20号外显子插入突变体中可恢复对dacomitinib的敏感性。基于这些结果，我们使用阿法替尼治疗了1例肿瘤携带HER 2 V777_G778insGSP突变的NSCLC患者，并获得了持久的部分缓解。我们进一步确定了EGFR（T790 M或C797 S）和HER 2（C805 S）中的继发性突变，这些突变在药物敏感性EGFR或HER 2 20号外显子插入模型中介导获得性耐药。总体而言，我们的研究结果确定了一个EGFR和HER 2 20号外显子插入突变子集，这些突变对现有的基于喹唑啉的共价EGFR/HER 2抑制剂敏感，对当前的临床治疗和下一代小分子抑制剂具有影响。
Insertion mutations in EGFR and HER2 both occur at analogous positions in exon 20. Non-small cell lung cancer (NSCLC) patients with tumors harboring these mutations seldom achieve clinical responses to dacomitinib and afatinib, two covalent quinazoline-based inhibitors of EGFR or HER2, respectively. In this study, we investigated the effects of specific EGFR and HER2 exon 20 insertion mutations from NSCLC patients that had clinically achieved a partial response after dacomitinib treatment. We identified Gly770 as a common feature among the drug-sensitive mutations. Structural modeling suggested that this mutation may facilitate inhibitor binding to EGFR. Introduction of Gly770 into two dacomitinib-resistant EGFR exon 20 insertion mutants restored sensitivity to dacomitinib. Based on these findings we used afatinib to treat a NSCLC patient whose tumor harbored the HER2 V777_G778insGSP mutation and achieved a durable partial response. We further identified secondary mutations in EGFR (T790M or C797S) and HER2 (C805S) that mediated acquired drug resistance in drug-sensitive EGFR or HER2 exon 20 insertion models. Overall, our findings identified a subset of EGFR and HER2 exon 20 insertion mutations that are sensitive to existing covalent quinazoline-based EGFR/HER2 inhibitors, with implications for current clinical treatment and next-generation small molecule inhibitors.