Research Papers:

Heterogeneity of resistance mutations detectable by next-generation sequencing in TKI-treated lung adenocarcinoma

Deborah A. Belchis, Li-Hui Tseng, Thomas Gniadek, Lisa Haley, Parvez Lokhandwala, Peter Illei, Christopher D. Gocke, Patrick Forde, Julie Brahmer, Frederic B. Askin, James R. Eshleman and Ming-Tseh Lin _

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Oncotarget. 2016; 7:45237-45248. https://doi.org/10.18632/oncotarget.9931

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Deborah A. Belchis1, Li-Hui Tseng1,2, Thomas Gniadek1, Lisa Haley1, Parvez Lokhandwala1, Peter Illei1, Christopher D. Gocke1,3, Patrick Forde3, Julie Brahmer3, Frederic B. Askin1, James R. Eshleman1,3, Ming-Tseh Lin1

1Department of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA

2Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan

3Department of Oncology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA

Correspondence to:

Deborah A. Belchis, email: [email protected]

Ming-Tseh Lin, email: [email protected]

Keywords: EGFR, PIK3CA, tyrosine kinase resistance, next-generation sequencing, lung cancer

Received: April 06, 2016     Accepted: May 19, 2016     Published: June 09, 2016


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.

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