Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M.
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.
AstraZeneca, Gatehouse Park, Waltham, Massachusetts, USA.
Kenneth S
KS
Thress
1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Cloud P
CP
Paweletz
1] Vall d'Hebron Institute of Oncology, Barcelona, Spain. [2] Vall d'Hebron University Hospital, Barcelona, Spain.
Enriqueta
E
Felip
Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
Byoung Chul
BC
Cho
AstraZeneca, Gatehouse Park, Waltham, Massachusetts, USA.
Daniel
D
Stetson
AstraZeneca, Gatehouse Park, Waltham, Massachusetts, USA.
Brian
B
Dougherty
AstraZeneca, Gatehouse Park, Waltham, Massachusetts, USA.
Zhongwu
Z
Lai
AstraZeneca, Gatehouse Park, Waltham, Massachusetts, USA.
Aleksandra
A
Markovets
Vall d'Hebron Institute of Oncology, Barcelona, Spain.
Ana
A
Vivancos
1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Yanan
Y
Kuang
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Dalia
D
Ercan
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Sarah E
SE
Matthews
AstraZeneca, Alderley Park, Macclesfield, UK.
Mireille
M
Cantarini
AstraZeneca, Gatehouse Park, Waltham, Massachusetts, USA.
J Carl
JC
Barrett
1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Pasi A
PA
Jänne
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Geoffrey R
GR
Oxnard
D000178:Acrylamides / Q000008:administration & dosage*; D000328:Adult; D000368:Aged; D000814:Aniline Compounds / Q000008:administration & dosage*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D007211:Indoles; D011743:Pyrimidines
D000178:Acrylamides; D000814:Aniline Compounds; D066246:ErbB Receptors; C000596361:osimertinib; D007211:Indoles; D011743:Pyrimidines; C512478:EGFR protein, human