Next-generation sequencing of tyrosine kinase inhibitor-resistant non-small-cell lung cancers in patients harboring epidermal growth factor-activating mutations

BMC Cancer

Research Article

Nobuyuki Katakami¹  Katsuhiro Masago¹  Ryoji Kato¹  Akito Hata¹  Kyoko Otsuka¹  Reiko Kaji¹  Yukio Hirata¹  Chiyuki Okuda¹  Jumpei Takeshita¹  Shiro Fujita¹  Miho Muraki² 

[1] Division of Integrated Oncology, Institute of Biomedical Research and Innovation, 2-2 Minatojima-minamimachi, Cyuo-ku, 650-0047, Kobe City, Hyogo, Japan;Thermo Fisher Scientific, Tokyo, Japan;

关键词: Acquired resistance;    Epidermal growth factor;    Next-generation sequencing;    Tyrosine kinase inhibitor;   

DOI  :  10.1186/s12885-015-1925-2

 received in 2015-02-10, accepted in 2015-11-11,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundThe aim of this study was to detect the epidermal growth factor receptor (EGFR)-activating mutations and other oncogene alterations in patients with non-small-cell lung cancers (NSCLC) who experienced a treatment failure in response to EGFR-tyrosine kinase inhibitors (TKIs) with a next generation sequencer.MethodsFifteen patients with advanced NSCLC previously treated with EGFR-TKIs were examined between August 2005 and October 2014. For each case, new biopsies were performed, followed by DNA sequencing on an Ion Torrent Personal Genome Machine (PGM) system using the Ion AmpliSeq Cancer Hotspot Panel version 2.ResultsAll 15 patients were diagnosed with NSCLC harboring EGFR-activating mutations (seven cases of exon 19 deletion, seven cases of L858R in exon 21, and one case of L861Q in exon 21). Of the 15 cases, acquired T790M resistance mutations were detected in 9 (60.0 %) patients. In addition, other mutations were identified outside of EGFR, including 13 cases (86.7 %) exhibiting TP53 P72R mutations, 5 cases (33.3 %) of KDR Q472H, and 2 cases (13.3 %) of KIT M541L.ConclusionsHere, we showed that next-generation sequencing (NGS) is able to detect EGFR T790M mutations in cases not readily diagnosed by other conventional methods. Significant differences in the degree of EGFR T790M and other EGFR-activating mutations may be indicative of the heterogeneity of disease phenotype evident within these patients. The co-existence of known oncogenic mutations within each of these patients may play a role in acquired EGFR-TKIs resistance, suggesting the need for alternative treatment strategies, with PCR-based NGS playing an important role in disease diagnosis.

【 授权许可】

CC BY   
© Masago et al. 2015