Epigenetic Regulation of EGFR-TKI Resistance in Non-Small Cell Lung Cancer: The Role of DNA/RNA Methylation and Non-Coding RNAs

The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) drugs represent the main targeted treatment modality for EGFR-mutant non-small cell lung cancer (NSCLC). However, acquired resistance develops in almost all cases. This focused review article provides insights into the epigenetic basis of resistance, presenting the relevant studies in the form of a ۴-dimensional matrix of: research focus (mechanism, detection/prognostication, effect on prognosis, therapeutic approach); resistance phenotype (resistance in tumors that remain NSCLC from the histological point of view or resistance in tumors that develop a phenotypic change from NSCLC to small cell lung cancer, SCLC); sample (histological tumor tissue or liquid biopsy); and the epigenetic alterations (DNA methylation, RNA methylation, histone modification, noncoding RNAs). Among the well-studied resistance mechanisms are DNMT۱-mediated hypermethylation, m۶A/m۵C RNA alterations, and microRNA/long noncoding RNAs. Particular emphasis is placed on the phenomenon of histological transformation to SCLC—epigenetically-driven highly aggressive resistance phenotype associated with RB۱/TP۵۳ inactivation and EZH۲/EHMT۲-mediated neuroendocrine conversion—as compared to other epigenetic resistance mechanisms, which maintain NSCLC histology. In addition, various shortcomings common to the whole body of knowledge about epigenetic mechanisms of resistance are discussed. They include biomarker specificity issues, difficulty distinguishing transformation from heterogeneous preexisting tumors, low numbers of transformation cases, the difference between tissue and liquid biopsies, and lack of prospective validation

کلیدواژه ها:

EGFR-TKI resistance ، non-small cell lung cancer ، DNA methylation ، RNA methylation (m۶A/m۵C) ، non-coding RNA