Identification of plasma microRNA profiles for primary resistance to EGFR-TKIs in advanced non-small cell lung cancer (NSCLC) patients with EGFR activating mutation

Journal of Hematology & Oncology

Jie Wang³  Jian Zhu²  Zhenxiang Li¹  Meina Wu¹  Zhijie Wang¹  Minglei Zhuo¹  Tongtong An¹  Jianchun Duan¹  Jun Zhao¹  Hua Bai¹  Xiaomei Su¹  Shuhang Wang¹ 

[1] The Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing, China;Department of Thoracic Medical Oncology, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing, 100036, China;Department of Bioscience and Nutrition, Novum, Karolinska Institute, Huddinge, 141 83, Sweden

关键词: microRNA and primary resistance;    EGFR 19 deletion mutation;    EGFR-TKI;   

Others  :  1233258
DOI  :  10.1186/s13045-015-0210-9

 received in 2015-05-25, accepted in 2015-09-28,  发布年份 2015

【 摘 要 】

Background

EGFR mutation is a strong predictor of efficacy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) therapy in advanced non-small cell lung cancer (NSCLC). However, around 20–30 % of EGFR-mutated cases showed no response to EGFR-TKIs, suggesting that other determinants beyond EGFR mutation likely exist. This study analyzed the role of microRNAs (miRNAs) in primary resistance to EGFR-TKIs in advanced NSCLC patients with EGFR mutation.

Methods

Training group: 20 advanced NSCLC patients with EGFR 19 deletion treated with first-line EGFR-TKIs were enrolled; half of them had dramatic responses while the other half had primary resistance. Matched plasma samples were collected for miRNA profiling using TaqMan low-density array (TLDA). Bioinformatics analyses were used to identify related miRNAs possibly accounted for resistance. Testing group: Quantitative reverse transcriptase PCR (qRT-PCR) was employed to detect the level of miRNA with significant differential expression in the training set. Validation group: Another cohort with EGFR 19 deletion mutations, who had dramatically different responses to EGFR-TKI, was used to validate the difference of miRNA expression between the sensitive and resistant groups using RT-PCR.

Results

Training group: 153 miRNAs were found to be differentially expressed between the sensitive and resistant groups. Potential target genes were predicted with a target scan database. Twelve differentially expressed miRNAs were selected for the analysis because of their known roles in tumorigenesis of lung cancer, resistance to drugs, and regulation of EGFR pathway. Training group: three out of the 12 miRNAs (miR-21, AmiR-27a, and miR-218) were verified to have significantly higher expression (P_{miR-21 = 0.004} , P_{miR-27a = 0.009} , P_{miR-218 = 0.041} , respectively) in the resistant group compared to the sensitive group. Validation group: The expression levels of these three miRNAs were validated to be significantly different (P = 0.011, 0.011, 0.026, respectively) in the validation cohort (n = 34).

Conclusions

Higher expression levels of miR-21, AmiR-27a, and miR-218 detected in this study suggest potential roles of these miRNAs in primary resistance to EGFR-TKI in advanced NSCLC patients with EGFR exon 19 deletion mutations. These findings need to be further confirmed in a study with a larger sample size.

【 授权许可】

   
2015 Wang et al.

【 图 表 】

Fig. 1.

Fig. 2.

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