High-Level Clonal FGFR Amplification and Response to FGFR Inhibition in a Translational Clinical Trial.
High-Level Clonal FGFR Amplification and Response to FGFR Inhibition in a Translational Clinical Trial.
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DOI：
10.1158/2159-8290.cd-15-1246
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发表时间：
2016-08
期刊：
影响因子：
28.2
通讯作者：
Turner NC
中科院分区：
文献类型：
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作者：
Pearson A;Smyth E;Babina IS;Herrera-Abreu MT;Tarazona N;Peckitt C;Kilgour E;Smith NR;Geh C;Rooney C;Cutts R;Campbell J;Ning J;Fenwick K;Swain A;Brown G;Chua S;Thomas A;Johnston SRD;Ajaz M;Sumpter K;Gillbanks A;Watkins D;Chau I;Popat S;Cunningham D;Turner NC
FGFR1和FGFR2在许多肿瘤类型中被扩增，但在被扩增的癌症中，决定对FGFR抑制的反应的因素尚不清楚。在一项翻译临床试验中，我们发现高水平克隆性FGFR2扩增的胃癌对选择性FGFR抑制剂AZD4547有很高的反应率，而亚克隆或低水平扩增的胃癌没有反应。利用细胞系和患者来源的异种移植模型，我们发现高水平的FGFR2扩增启动了一种独特的癌基因成瘾表型，其特征是FGFR2介导的替代受体激酶的反式激活，使PI3K/mTOR信号处于FGFR控制之下。在低水平的FGFR1扩增的癌症中，信号更多地限于MAPK信号，限制了对FGFR抑制的敏感性。最后，我们展示了循环肿瘤DNA筛查可以识别高水平克隆扩增的癌症。我们的数据提供了对在高度放大的癌症中所见的癌基因成瘾的独特模式的机械性理解，并证明了克隆在预测靶向治疗的反应中的重要性。只有在高水平的FGFR扩增的癌症中才能看到对FGFR抑制的强大单剂反应，在体外、体内和临床上，拷贝数水平决定了对FGFR抑制的反应。FGFR2的高水平扩增在胃癌和乳腺癌中相对罕见，我们表明，在循环肿瘤DNA中进行扩增的筛查可能为筛查患者提供了一种可行的策略。
FGFR1 and FGFR2 are amplified in many tumor types, yet what determines response to FGFR inhibition in amplified cancers is unknown. In a translational clinical trial, we show that gastric cancers with high-level clonal FGFR2 amplification have a high response rate to the selective FGFR inhibitor AZD4547, whereas cancers with subclonal or low-level amplification did not respond. Using cell lines and patient-derived xenograft models, we show that high-level FGFR2 amplification initiates a distinct oncogene addiction phenotype, characterized by FGFR2-mediated transactivation of alternative receptor kinases, bringing PI3K/mTOR signaling under FGFR control. Signaling in low-level FGFR1-amplified cancers is more restricted to MAPK signaling, limiting sensitivity to FGFR inhibition. Finally, we show that circulating tumor DNA screening can identify high-level clonally amplified cancers. Our data provide a mechanistic understanding of the distinct pattern of oncogene addiction seen in highly amplified cancers and demonstrate the importance of clonality in predicting response to targeted therapy. Robust single-agent response to FGFR inhibition is seen only in high-level FGFR-amplified cancers, with copy-number level dictating response to FGFR inhibition in vitro, in vivo, and in the clinic. High-level amplification of FGFR2 is relatively rare in gastric and breast cancers, and we show that screening for amplification in circulating tumor DNA may present a viable strategy to screen patients.