| Summary: | Osimertinib has been an effective second-line treatment in EGFR mutant NSCLC patients; however, resistance inevitably occurs. DNA methylation has been previously implicated in NSCLC progression and often in therapy resistance, however its distinct role in osimertinib resistance is not elucidated as yet. In the present study, we directly compared DNA methylation of nine selected genes (<i>RASSF1A</i>, <i>RASSF10</i>, <i>APC</i>, <i>WIF-1</i>, <i>BRMS1</i>, <i>SLFN11</i>, <i>RARβ</i>, <i>SHISA3</i>, and <i>FOXA1</i>) in plasma-cfDNA and paired CTCs of NSCLC patients who were longitudinally monitored during osimertinib treatment. Peripheral blood (PB) from 42 NSCLC patients was obtained at two time points: (a) baseline: before treatment with osimertinib and (b) at progression of disease (PD). DNA methylation of the selected genes was detected in plasma-cfDNA (<i>n</i> = 80) and in paired CTCs (<i>n</i> = 74). Direct comparison of DNA methylation of six genes between plasma-cfDNA and paired CTC samples (<i>n</i> = 70) revealed a low concordance, indicating that CTCs and cfDNA give complementary information. DNA methylation analysis of plasma-cfDNA and CTCs indicated that when at least one of these genes was methylated there was a statistically significant increase at PD compared to baseline (<i>p</i> = 0.031). For the first time, DNA methylation analysis in plasma-cfDNA and paired CTCs of NSCLC patients during osimertinib therapy indicated that DNA methylation of these genes could be a possible resistance mechanism.
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