期刊
NATURE COMMUNICATIONS
卷 7, 期 -, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/ncomms11815
关键词
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资金
- National Science Foundation [DGE-114747]
- Department of Defense
- National Cancer Institute [R01CA188298]
- US National Institutes of Health Director's New Innovator Award [1-DP2-CA186569]
- Ludwig Institute for Cancer Research
- Stanford Cancer Institute-Developmental Cancer Research Award
- CRK Faculty Scholar Fund
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 similar to 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.
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