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; Maximilian Diehn

doi:10.1038/ncomms11815

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

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

Authors

Jacob J Chabon^{1

2}, Andrew D Simmons³, Alexander F Lovejoy^{1

2}, Mohammad S Esfahani^{1

2}, Aaron M Newman^{1

2}, Henry J Haringsma³, David M Kurtz^{4

5}, Henning Stehr^{1

2}, Florian Scherer^{2

4}, Chris A Karlovich³, Thomas C Harding³, Kathleen A Durkin⁶, Gregory A Otterson⁷, W Thomas Purcell⁸, D Ross Camidge⁸, Jonathan W Goldman⁹, Lecia V Sequist¹⁰, Zofia Piotrowska¹⁰, Heather A Wakelee⁴, Joel W Neal⁴, Ash A Alizadeh^{1

2

4

11}, Maximilian Diehn^{1

2

12}

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Acrylamides / pharmacology
Acrylamides / therapeutic use
Carcinoma, Non-Small-Cell Lung / drug therapy
Carcinoma, Non-Small-Cell Lung / genetics
Carcinoma, Non-Small-Cell Lung / pathology
Circulating Tumor DNA / metabolism*
Cohort Studies
Crizotinib
Drug Resistance, Neoplasm / drug effects*
Drug Resistance, Neoplasm / genetics
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / metabolism
Gene Amplification
Gene Dosage
Genetic Heterogeneity
Humans
Lung Neoplasms / drug therapy
Lung Neoplasms / genetics*
Lung Neoplasms / pathology*
Mutation / genetics
Protein Kinase Inhibitors / pharmacology*
Protein Kinase Inhibitors / therapeutic use
Proto-Oncogene Proteins c-met / genetics
Proto-Oncogene Proteins c-met / metabolism
Pyrazoles / pharmacology
Pyrazoles / therapeutic use
Pyridines / pharmacology
Pyridines / therapeutic use
Pyrimidines / pharmacology
Pyrimidines / therapeutic use
Xenograft Model Antitumor Assays

Substances

Acrylamides
Circulating Tumor DNA
Protein Kinase Inhibitors
Pyrazoles
Pyridines
Pyrimidines
Crizotinib
rociletinib
ErbB Receptors
Proto-Oncogene Proteins c-met

Abstract

Publication types

MeSH terms

Substances

Grants and funding