Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients.
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.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California 94305, USA.|Stanford Cancer Institute, Stanford University, Stanford, California 94305, USA.
Jacob J
JJ
Chabon
Clovis Oncology, Inc., San Francisco, California 94158, USA.
Andrew D
AD
Simmons
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California 94305, USA.|Stanford Cancer Institute, Stanford University, Stanford, California 94305, USA.
Alexander F
AF
Lovejoy
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California 94305, USA.|Stanford Cancer Institute, Stanford University, Stanford, California 94305, USA.
Mohammad S
MS
Esfahani
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California 94305, USA.|Stanford Cancer Institute, Stanford University, Stanford, California 94305, USA.
Aaron M
AM
Newman
Clovis Oncology, Inc., San Francisco, California 94158, USA.
Henry J
HJ
Haringsma
Division of Oncology, Department of Medicine, Stanford University, Stanford, California 94305, USA.|Department of Bioengineering, Stanford University, Stanford, California 94305, USA.
David M
DM
Kurtz
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California 94305, USA.|Stanford Cancer Institute, Stanford University, Stanford, California 94305, USA.
Henning
H
Stehr
Stanford Cancer Institute, Stanford University, Stanford, California 94305, USA.|Division of Oncology, Department of Medicine, Stanford University, Stanford, California 94305, USA.
Florian
F
Scherer
Clovis Oncology, Inc., San Francisco, California 94158, USA.
Chris A
CA
Karlovich
Clovis Oncology, Inc., San Francisco, California 94158, USA.
Thomas C
TC
Harding
Molecular Graphics and Computation Facility, College of Chemistry, University of California, Berkeley, California 94720, USA.
Kathleen A
KA
Durkin
The Ohio State University, Columbus, Ohio 43210, USA.
Gregory A
GA
Otterson
Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
W Thomas
WT
Purcell
Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
D Ross
DR
Camidge
David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA.
Jonathan W
JW
Goldman
Massachusetts General Hospital &Harvard Medical School, Boston, Massachusetts 02115, USA.
Lecia V
LV
Sequist
Massachusetts General Hospital &Harvard Medical School, Boston, Massachusetts 02115, USA.
Zofia
Z
Piotrowska
Division of Oncology, Department of Medicine, Stanford University, Stanford, California 94305, USA.
Heather A
HA
Wakelee
Division of Oncology, Department of Medicine, Stanford University, Stanford, California 94305, USA.
Joel W
JW
Neal
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California 94305, USA.|Stanford Cancer Institute, Stanford University, Stanford, California 94305, USA.|Division of Oncology, Department of Medicine, Stanford University, Stanford, California 94305, USA.|Division of Hematology, Department of Medicine, Stanford University, Stanford, California 94305, USA.
Ash A
0000-0002-5153-5625
AA
Alizadeh
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California 94305, USA.|Stanford Cancer Institute, Stanford University, Stanford, California 94305, USA.|Department of Radiation Oncology, Stanford University, Stanford, California 94305, USA.
Maximilian
0000-0003-2032-0581
M
Diehn
D000178:Acrylamides / Q000494:pharmacology / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D000074141:Circulating Tumor DNA / Q000378:metabolism*; D015331:Cohort Studies; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005784:Gene Amplification; D018628:Gene Dosage; D018740:Genetic Heterogeneity; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
D000178:Acrylamides; D000074141:Circulating Tumor DNA; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D000077547:Crizotinib; C000589977:rociletinib; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met