YES1 amplification: a mechanism of acquired resistance to EGFR inhibitors identified by transposon mutagenesis and clinical genomics-猫眼课题宝

DOI：

10.1101/275974

发表时间：

2018-03

期刊：

bioRxiv

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

P. Fan;G. Narzisi;A. Jayaprakash;E. Venturini;N. Robine;Peter Smibert;S. Germer;H. Yu;E. Jordan;P. Paik;Y. Janjigian;J. Chaft;Lu Wang;A. Jungbluth;S. Middha;L. Spraggon;H. Qiao;C. Lovly;M. Kris;Gregory Riely;K. Politi;H. Varmus;M. Ladanyi

在大约30%的EGFR突变肺腺癌患者中，他们的疾病进展是通过EGFR抑制剂进行的，获得性耐药性的基础仍然不清楚。我们集成了在EGFR突变细胞系中的转座子突变筛选和获得性耐药病例的临床基因组测序，以确定对EGFR抑制剂耐药的新机制。通过在筛选过程中插入或靠近基因而确定的最突出的候选基因被遇到，该基因的扩增被认为是介导对EGFR抑制剂的抗性的基因，以及编码Src家族激酶YES1的基因。具有激活YES1表达的转座子插入的细胞克隆表现出对所有三代EGFR抑制剂的抗性，以及对药物和siRNA介导的YES1抑制的敏感性。对EGFR抑制剂获得性耐药病例的临床基因组测序数据分析显示，5例YES1基因扩增，其中4例缺乏任何其他已知的耐药机制。5名患者中有2名患者可获得的前抑制物样本缺乏YES1扩增。在136个抑制剂后样本中，没有一例检测到其他Src家族激酶(SRC、FYN)的扩增。在17例ALK融合阳性肺癌患者的ALK TKIs进展中，也有2例发现YES1扩增。综上所述，我们的发现确认YES1的获得性扩增是EGFR突变肺癌耐受EGFR抑制的一种新的、重复的和靶向的机制，并证明了转座子突变在发现临床相关耐药机制方面的作用。意义尽管对EGFR酪氨酸激酶活性的小分子抑制剂的治疗有很高的应答率，但EGFR突变的肺腺癌患者最终对这些药物产生耐药性。在许多情况下，获得性抵抗力的基础仍然不清楚。我们在EGFR突变细胞系中使用了转座子突变筛选，并在获得性耐药病例中进行了临床基因组测序，以确定YES1扩增是EGFR突变肺癌耐药的一种新的和靶向的机制。

In approximately 30% of patients with EGFR-mutant lung adenocarcinomas whose disease progresses on EGFR inhibitors, the basis for acquired resistance remains unclear. We have integrated transposon mutagenesis screening in an EGFR-mutant cell line and clinical genomic sequencing in cases of acquired resistance to identify novel mechanisms of resistance to EGFR inhibitors. The most prominent candidate genes identified by insertions in or near the genes during the screen were MET, a gene whose amplification is known to mediate resistance to EGFR inhibitors, and the gene encoding the Src family kinase YES1. Cell clones with transposon insertions that activated expression of YES1 exhibited resistance to all three generations of EGFR inhibitors and sensitivity to pharmacologic and siRNA-mediated inhibition of YES1. Analysis of clinical genomic sequencing data from cases of acquired resistance to EGFR inhibitors revealed amplification of YES1 in 5 cases, 4 of which lacked any other known mechanisms of resistance. Pre-inhibitor samples, available for 2 of the 5 patients, lacked YES1 amplification. None of 136 post-inhibitor samples had detectable amplification of other Src family kinases (SRC, FYN). YES1 amplification was also found in 2 of 17 samples from ALK fusion-positive lung cancer patients who had progressed on ALK TKIs. Taken together, our findings identify acquired amplification of YES1 as a novel, recurrent, and targetable mechanism of resistance to EGFR inhibition in EGFR-mutant lung cancers, and demonstrate the utility of transposon mutagenesis in discovering clinically relevant mechanisms of drug resistance. SIGNIFICANCE Despite high response rates to treatment with small molecule inhibitors of EGFR tyrosine kinase activity, patients with EGFR-mutant lung adenocarcinomas eventually develop resistance to these drugs. In many cases, the basis of acquired resistance remains unclear. We have used a transposon mutagenesis screen in an EGFR-mutant cell line and clinical genomic sequencing in cases of acquired resistance to identify amplification of YES1 as a novel and targetable mechanism of resistance to EGFR inhibitors in EGFR-mutant lung cancers.

YES1 amplification: a mechanism of acquired resistance to EGFR inhibitors identified by transposon mutagenesis and clinical genomics

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