EGFR Kinase Domain Duplication (EGFR-KDD) Is a Novel Oncogenic Driver in Lung Cancer That Is Clinically Responsive to Afatinib.
EGFR Kinase Domain Duplication (EGFR-KDD) Is a Novel Oncogenic Driver in Lung Cancer That Is Clinically Responsive to Afatinib.
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DOI：
10.1158/2159-8290.cd-15-0654
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发表时间：
2015-11
期刊：
影响因子：
28.2
通讯作者：
Lovly CM
中科院分区：
文献类型：
--
作者：
Gallant JN;Sheehan JH;Shaver TM;Bailey M;Lipson D;Chandramohan R;Red Brewer M;York SJ;Kris MG;Pietenpol JA;Ladanyi M;Miller VA;Ali SM;Meiler J;Lovly CM
在10-35%的肺腺癌中发现了致癌性EGFR突变。此类突变最常见的表现为外显子19中的小框内缺失或外显子21中的点突变（L 858 R），赋予对EGFR酪氨酸激酶抑制剂（TKI）的敏感性。在分析一位33岁从不吸烟的男性肺癌患者的肿瘤时，我们发现了一种新的肺癌EGFR改变：EGFR外显子18-25激酶结构域重复（EGFR-KDD）。通过分析更大的肿瘤样本队列，我们在肺癌、脑癌和其他癌症中检测到了EGFR-KDD的额外病例。在体外，EGFR-KDD是组成性激活的，计算模型为其自动激活提供了潜在的机制支持。EGFR-KDD转化细胞对EGFR TKI敏感，与这些体外结果一致，索引患者对EGFR TKI阿法替尼有部分缓解。患者最终进展，此时，重新测序显示了对阿法替尼获得性耐药的EGFR依赖性机制，从而验证了EGFR-KDD作为驱动改变和治疗靶点。
Oncogenic EGFR mutations are found in 10-35% of lung adenocarcinomas. Such mutations, which present most commonly as small in-frame deletions in exon 19 or point mutations in exon 21 (L858R), confer sensitivity to EGFR tyrosine kinase inhibitors (TKIs). In analyzing the tumor from a 33-year-old male never smoker, we identified a novel EGFR alteration in lung cancer: EGFR exon 18-25 kinase domain duplication (EGFR-KDD). Through analysis of a larger cohort of tumor samples, we detected additional cases of EGFR-KDD in lung, brain, and other cancers. In vitro, EGFR-KDD is constitutively active, and computational modeling provides potential mechanistic support for its auto-activation. EGFR-KDD-transformed cells are sensitive to EGFR TKIs and, consistent with these in vitro findings, the index patient had a partial response to the EGFR TKI, afatinib. The patient eventually progressed, at which time, re-sequencing revealed an EGFR-dependent mechanism of acquired resistance to afatinib, thereby validating EGFR-KDD as a driver alteration and therapeutic target.