Heterogeneity of resistance mutations detectable by nextgeneration sequencing in TKI-treated lung adenocarcinoma
Journal
Oncotarget
Journal Volume
7
Journal Issue
29
Pages
45237-45248
Date Issued
2016
Author(s)
Belchis D.A.
Gniadek T.
Haley L.
Lokhandwala P.
Illei P.
Gocke C.D.
Forde P.
Brahmer J.
Askin F.B.
Eshleman J.R.
Lin M.-T.
Abstract
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.
Subjects
EGFR; Lung cancer; Next generation sequencing; PIK3CA; Tyrosine kinase resistance
SDGs
Other Subjects
epidermal growth factor receptor; erlotinib; gefitinib; protein tyrosine kinase inhibitor; epidermal growth factor receptor; KRAS protein, human; phosphatidylinositol 4,5 bisphosphate 3 kinase; PIK3CA protein, human; protein kinase inhibitor; protein p21; Article; cancer resistance; clinical article; codon; cohort analysis; controlled study; epidermal growth factor receptor gene; exon; gene; gene frequency; gene mutation; human; human tissue; lung adenocarcinoma; next generation sequencing; oncogene K ras; PIK3CA gene; retrospective study; single nucleotide polymorphism; small cell lung cancer; adenocarcinoma; drug resistance; genetics; high throughput sequencing; lung tumor; mutation; Adenocarcinoma; Class I Phosphatidylinositol 3-Kinases; Drug Resistance, Neoplasm; Gene Frequency; High-Throughput Nucleotide Sequencing; Humans; Lung Neoplasms; Mutation; Polymorphism, Single Nucleotide; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Receptor, Epidermal Growth Factor
Publisher
Impact Journals LLC
Type
journal article