Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients.
Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients.
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DOI：
10.1038/ncomms11815
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发表时间：
2016-06-10
影响因子：
16.6
通讯作者：
Diehn M
中科院分区：
文献类型：
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作者：
Chabon JJ;Simmons AD;Lovejoy AF;Esfahani MS;Newman AM;Haringsma HJ;Kurtz DM;Stehr H;Scherer F;Karlovich CA;Harding TC;Durkin KA;Otterson GA;Purcell WT;Camidge DR;Goldman JW;Sequist LV;Piotrowska Z;Wakelee HA;Neal JW;Alizadeh AA;Diehn M
循环肿瘤DNA（ctDNA）分析促进了肿瘤异质性的研究。在这里，我们采用CAPP-Seq ctDNA分析来研究43例接受第三代表皮生长因子受体（EGFR）抑制剂rociletinib治疗的非小细胞肺癌（NSCLC）患者的耐药机制。我们观察到46%的患者在一线抑制剂治疗后存在多种耐药机制，表明患者内异质性频繁。Rociletinib耐药复发涉及MET、EGFR、PIK 3CA、ERRB 2、KRAS和RB 1。我们描述了一种新的EGFR L798 I突变，发现在奥希替尼治疗后约33%的患者中出现EGFR C797 S，而在rociletinib治疗后发生率<3%。MET拷贝数增加是该队列中最常见的rociletinib耐药机制，具有多种既存机制（T790 M和MET）的患者的疗效较差。类似地，rociletinib耐药异种移植物发生MET扩增，MET抑制剂克唑替尼可以克服这种扩增。这些结果强调了肿瘤异质性在NSCLC中的重要性以及基于ctDNA的耐药机制评估的实用性。 EGFR突变型非小细胞肺癌通常用EGFR抑制剂治疗，尽管不可避免地会产生耐药性。在这里，作者对循环肿瘤DNA进行测序，并表明对第三代抑制剂rociletinib的耐药性是异质性的，并且反复涉及MET，EGFR，PIK 3CA，ERRB 2和KRAS的体细胞改变。
Circulating tumour DNA (ctDNA) analysis facilitates studies of tumour heterogeneity. Here we employ CAPP-Seq ctDNA analysis to study resistance mechanisms in 43 non-small cell lung cancer (NSCLC) patients treated with the third-generation epidermal growth factor receptor (EGFR) inhibitor rociletinib. We observe multiple resistance mechanisms in 46% of patients after treatment with first-line inhibitors, indicating frequent intra-patient heterogeneity. Rociletinib resistance recurrently involves MET, EGFR, PIK3CA, ERRB2, KRAS and RB1. We describe a novel EGFR L798I mutation and find that EGFR C797S, which arises in ∼33% of patients after osimertinib treatment, occurs in <3% after rociletinib. Increased MET copy number is the most frequent rociletinib resistance mechanism in this cohort and patients with multiple pre-existing mechanisms (T790M and MET) experience inferior responses. Similarly, rociletinib-resistant xenografts develop MET amplification that can be overcome with the MET inhibitor crizotinib. These results underscore the importance of tumour heterogeneity in NSCLC and the utility of ctDNA-based resistance mechanism assessment. EGFR-mutant non-small cell lung cancer is routinely treated with EGFR inhibitors, although resistance inevitably develops. Here, the authors sequence circulating tumour DNA and show that resistance to the third-generation inhibitor rociletinib is heterogeneous and recurrently involves somatic alterations of MET, EGFR, PIK3CA, ERRB2, and KRAS.