J Cancer 2019; 10(7):1726-1733. doi:10.7150/jca.26482

Research Paper

P16 Methylation Leads to Paclitaxel Resistance of Advanced Non-Small Cell Lung Cancer

Zhaojun Liu1*, Hongmei Lin2,3*, Ying Gan1, Chenghua Cui1, Baozhen Zhang1, Liankun Gu1, Jing Zhou1, Guangying Zhu2,3✉, Dajun Deng1✉

1. Key Laboratory of Carcinogenesis and Translational Research, Division of Etiology,
2. Key Laboratory of Carcinogenesis and Translational Research, Department of Radiation Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142;
3. National Clinical Research Center for Respiratory Diseases, Department of Radiation Oncology, China-Japan Friendship Hospital, Beijing, 100029, China
*Equal contribution

Abstract

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.

Keywords: P16, methylation, paclitaxel, resistance, non-small cell lung cancer

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How to cite this article:
Liu Z, Lin H, Gan Y, Cui C, Zhang B, Gu L, Zhou J, Zhu G, Deng D. P16 Methylation Leads to Paclitaxel Resistance of Advanced Non-Small Cell Lung Cancer. J Cancer 2019; 10(7):1726-1733. doi:10.7150/jca.26482. Available from http://www.jcancer.org/v10p1726.htm