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Nat Commun. 2016 Jun 10;7:11815. doi: 10.1038/ncomms11815.

Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients.

Author information

1
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California 94305, USA.
2
Stanford Cancer Institute, Stanford University, Stanford, California 94305, USA.
3
Clovis Oncology, Inc., San Francisco, California 94158, USA.
4
Division of Oncology, Department of Medicine, Stanford University, Stanford, California 94305, USA.
5
Department of Bioengineering, Stanford University, Stanford, California 94305, USA.
6
Molecular Graphics and Computation Facility, College of Chemistry, University of California, Berkeley, California 94720, USA.
7
The Ohio State University, Columbus, Ohio 43210, USA.
8
Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
9
David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA.
10
Massachusetts General Hospital &Harvard Medical School, Boston, Massachusetts 02115, USA.
11
Division of Hematology, Department of Medicine, Stanford University, Stanford, California 94305, USA.
12
Department of Radiation Oncology, Stanford University, Stanford, California 94305, USA.

Abstract

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.

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