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

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-6-Methyladenosine (m(6)A) modification. First, we depicted the m(6)A 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 m(6)A-modified genes, which were the intersection of the differentially m(6)A methylated genes and the differentially expressed genes between H1299 and A549, as well as negative correlation between m(6)A modification levels and gene expression levels. In addition, functional enrichment analysis of the functionally m(6)A-modified genes indicated that m(6)A methylation might modify cell cycle to affect afatinib response. Furthermore, the functionally m(6)A-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 m(6)A modification could affect prognosis of NSCLC patients. In conclusion, we conducted a first attempt to dissect m(6)A methylation affection on afatinib resistance in NSCLC, and brought inspiration for the study of epigenetic roles in drug resistance.