Heterogeneity of resistance mutations detectable by nextgeneration sequencing in TKI-treated lung adenocarcinoma.
EGFR-mutated lung adenocarcinomas routinely develop resistance to tyrosine kinase inhibitors (TKI). To better characterize the relative frequencies of the resistance mechanisms, we analyzed 48 EGFR-mutated TKI-resistant specimens from 41 patients. Next-generation sequencing of post-treatment specimens detected EGFR p.T790M in 31 (79%) of 39 patients, PIK3CA mutations in 10 (26%), EGFR p.S768_V769delinsIL in one, and KRAS p.G12C in one. Five PIK3CA mutations were outside of codons 542, 545, and 1047. Three of four pre-treatment specimens did not carry the PIK3CA mutation found in the post-treatment sample. Small cell carcinoma transformation was identified in four patients; none had p.T790M, including two where p.T790M was identified in the co-existing adenocarcinoma. In p.T790M-mutated specimens, the allele frequency was less than 5% in 24% of cases. p.T790M allele frequency was usually lower than that of the sensitizing mutation indicating that the resistance mutation was present either in a subset of cells or, if the sensitizing mutation was amplified, in a subset of the sensitizing alleles of a dominant clone. Eight patients had multiple resistance mutations, suggesting either multiple separate resistant clones or a single clone harboring multiple resistance mechanisms. PIK3CA mutations appear to be a more significant resistance mechanism than previously recognized.
Department of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA.
Deborah A
DA
Belchis
Department of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA.|Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.
Li-Hui
LH
Tseng
Department of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA.
Thomas
T
Gniadek
Department of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA.
Lisa
L
Haley
Department of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA.
Parvez
P
Lokhandwala
Department of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA.
Peter
P
Illei
Department of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA.|Department of Oncology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA.
Christopher D
CD
Gocke
Department of Oncology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA.
Patrick
P
Forde
Department of Oncology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA.
Julie
J
Brahmer
Department of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA.
Frederic B
FB
Askin
Department of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA.|Department of Oncology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA.
James R
JR
Eshleman
Department of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA.
Ming-Tseh
MT
Lin
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics; D000077192:Adenocarcinoma of Lung; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics; D005787:Gene Frequency; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics
C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras)
EGFR; PIK3CA; lung cancer; next-generation sequencing; tyrosine kinase resistance