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Pharmacogenomics J. 2019 Oct 17. doi: 10.1038/s41397-019-0110-4. [Epub ahead of print]

Dissecting the m6A methylation affection on afatinib resistance in non-small cell lung cancer.

Author information

1
College of Bioinformatics Science and Technology, Harbin Medical University, 150081, Harbin, China.
2
College of Automation Engineering, Nanjing University of Aeronautics and Astronautics, 211106, Nanjing, China.
3
College of Bioinformatics Science and Technology, Harbin Medical University, 150081, Harbin, China. chaohanxu@hrbmu.edu.cn.
4
College of Bioinformatics Science and Technology, Harbin Medical University, 150081, Harbin, China. weijiang@nuaa.edu.cn.
5
College of Automation Engineering, Nanjing University of Aeronautics and Astronautics, 211106, Nanjing, China. weijiang@nuaa.edu.cn.

Abstract

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer deaths. Afatinib is the first-line anti-cancer agent for treatment of NSCLC. However, unexpected resistance has been a major obstacle for its clinical efficacy. In this study, we dissected afatinib resistance from the perspective of N6-Methyladenosine (m6A) modification. First, we depicted the m6A modification profiles for the afatinib resistant and sensitive NSCLC cell lines (H1299 and A549). We found that the sum enrichment scores of the resistant cell line (H1299) was much higher than that of the sensitive cell line (A549). Next, we identified the functionally m6A-modified genes, which were the intersection of the differentially m6A methylated genes and the differentially expressed genes between H1299 and A549, as well as negative correlation between m6A modification levels and gene expression levels. In addition, functional enrichment analysis of the functionally m6A-modified genes indicated that m6A methylation might modify cell cycle to affect afatinib response. Furthermore, the functionally m6A-modified genes were over-represented in the putative drug resistance-associated genes and the FDA-approved drug targets, and had significantly higher average degree and clustering coefficient than other genes in protein-protein interaction (PPI) network. We also identified five network modules, which were all related to drug resistance functions. Finally, survival analysis demonstrated that m6A modification could affect prognosis of NSCLC patients. In conclusion, we conducted a first attempt to dissect m6A methylation affection on afatinib resistance in NSCLC, and brought inspiration for the study of epigenetic roles in drug resistance.

PMID:
31624334
DOI:
10.1038/s41397-019-0110-4

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