Pharmacogenomics J
College of Bioinformatics Science and Technology, Harbin Medical University, 150081, Harbin, China.
Published: April 2020
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 N-Methyladenosine (mA) modification. First, we depicted the mA 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 mA-modified genes, which were the intersection of the differentially mA methylated genes and the differentially expressed genes between H1299 and A549, as well as negative correlation between mA modification levels and gene expression levels. In addition, functional enrichment analysis of the functionally mA-modified genes indicated that mA methylation might modify cell cycle to affect afatinib response. Furthermore, the functionally mA-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 mA modification could affect prognosis of NSCLC patients. In conclusion, we conducted a first attempt to dissect mA methylation affection on afatinib resistance in NSCLC, and brought inspiration for the study of epigenetic roles in drug resistance.
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http://dx.doi.org/10.1038/s41397-019-0110-4 | DOI Listing |
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