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Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M

 Kenneth S Thress  ;  Cloud P Paweletz  ;  Enriqueta Felip  ;  Byoung Chul Cho  ;  Daniel Stetson  ;  Brian Dougherty  ;  Zhongwu Lai  ;  Aleksandra Markovets  ;  Ana Vivancos  ;  Yanan Kuang  ;  Dalia Ercan  ;  Sarah E Matthews  ;  Mireille Cantarini  ;  J Carl Barrett  ;  Pasi A Jänne  ;  Geoffrey R Oxnard 
 NATURE MEDICINE, Vol.21(6) : 560-562, 2015 
Journal Title
Issue Date
Acrylamides/administration & dosage* ; Adult ; Aged ; Aniline Compounds/administration & dosage* ; Carcinoma, Non-Small-Cell Lung/drug therapy* ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/pathology ; Drug Resistance, Neoplasm ; Female ; High-Throughput Nucleotide Sequencing ; Humans ; Male ; Middle Aged ; Mutation ; Receptor, Epidermal Growth Factor/genetics*
Here we studied cell-free plasma DNA (cfDNA) collected from subjects with advanced lung cancer whose tumors had developed resistance to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) AZD9291. We first performed next-generation sequencing of cfDNA from seven subjects and detected an acquired EGFR C797S mutation in one; expression of this mutant EGFR construct in a cell line rendered it resistant to AZD9291. We then performed droplet digital PCR on serial cfDNA specimens collected from 15 AZD9291-treated subjects. All were positive for the T790M mutation before treatment, but upon developing AZD9291 resistance three molecular subtypes emerged: six cases acquired the C797S mutation, five cases maintained the T790M mutation but did not acquire the C797S mutation and four cases lost the T790M mutation despite the presence of the underlying EGFR activating mutation. Our findings provide insight into the diversity of mechanisms through which tumors acquire resistance to AZD9291 and highlight the need for therapies that are able to overcome resistance mediated by the EGFR C797S mutation.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Cho, Byoung Chul(조병철) ORCID logo https://orcid.org/0000-0002-5562-270X
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