Paclitaxel-based
chemotherapy is widely used as the first-line treatment for
non-small cell lung cancer (NSCLC). However, only 20%-40% of patients have shown sensitivity to
paclitaxel. This study aimed to investigate whether P16 methylation could be used to predict
paclitaxel chemosensitivity of NSCLC. Advanced NSCLC (N=45) were obtained from patients who were enrolled in a phase-III randomized
paclitaxel-based clinical trial. Genomic
DNA samples were extracted from the biopsies prior to
chemotherapy. P16 methylation was detected using MethyLight. The association between P16 methylation and the sensitivity of
paclitaxel in cell lines was determined by in vitro assay using a P16-specific
DNA demethylase (P16-TET) and
methyltransferase (P16-Dnmt). The total response rate of the low-dose
paclitaxel-based chemo-
radiotherapy was significantly lower in P16 methylation-positive NSCLCs than that in the P16 methylation-negative NSCLCs (2/15 vs. 16/30: adjusted OR=0.085; 95%CI, 0.012-0.579). Results revealed that P16 demethylation significantly decreased
paclitaxel resistance of
lung cancer H1299 cells (IC50 values decreased from 2.15 to 1.13 µg/ml, P<0.001). In contrast, P16-specific methylation by P16-Dnmt significantly increased
paclitaxel resistance of
lung cancer HCC827 cells and
gastric cancer BGC823 cells (IC50 values increased from 18.2 to 24.0 ng/ml and 0.18 to 0.81 µg/ml, respectively; P=0.049 and <0.001, respectively). The present results suggest that P16 methylation may lead to
paclitaxel resistance and be a predictor of
paclitaxel chemosensitivity of NSCLC.