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

Jacob J. Chabon, Andrew D. Simmons, Alexander F. Lovejoy, Mohammad S. Esfahani, Aaron M. Newman, Henry J. Haringsma, David M. Kurtz, Henning Stehr, Florian Scherer, Chris A. Karlovich, Thomas C. Harding, Kathleen A. Durkin, Gregory A. Otterson, W. Thomas Purcell, D. Ross Camidge, Jonathan W. Goldman, Lecia V. Sequist, Zofia Piotrowska, Heather A. Wakelee, Joel W. Neal, Ash A. Alizadeh () and Maximilian Diehn ()
Additional contact information
Jacob J. Chabon: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University
Andrew D. Simmons: Clovis Oncology, Inc.
Alexander F. Lovejoy: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University
Mohammad S. Esfahani: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University
Aaron M. Newman: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University
Henry J. Haringsma: Clovis Oncology, Inc.
David M. Kurtz: Stanford University
Henning Stehr: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University
Florian Scherer: Stanford Cancer Institute, Stanford University
Chris A. Karlovich: Clovis Oncology, Inc.
Thomas C. Harding: Clovis Oncology, Inc.
Kathleen A. Durkin: Molecular Graphics and Computation Facility, College of Chemistry, University of California
Gregory A. Otterson: The Ohio State University
W. Thomas Purcell: University of Colorado School of Medicine
D. Ross Camidge: University of Colorado School of Medicine
Jonathan W. Goldman: David Geffen School of Medicine, University of California, Los Angeles
Lecia V. Sequist: Massachusetts General Hospital & Harvard Medical School
Zofia Piotrowska: Massachusetts General Hospital & Harvard Medical School
Heather A. Wakelee: Stanford University
Joel W. Neal: Stanford University
Ash A. Alizadeh: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University
Maximilian Diehn: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: 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

Date: 2016
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DOI: 10.1038/ncomms11815

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