A novel strategy of EGFR-TKI combined chemotherapy in the treatment of human lung cancer with EGFR-sensitive mutation

作者：Zhang, Lanlin; Qi, Yuan; Xing, Kailin; Qian, Song; Zhang, Ping; Wu, Xianghua^*

来源：Oncology Reports, 2018, 40(2): 1046-1054.

DOI：10.3892/or.2018.6499

• epidermal growth factor receptor
• tyrosine kinase inhibitor
• chemotherapy
• heterogeneity
• cell cycle
• lung cancer

The discovery of epidermal growth factor receptor (EGFR)-sensitive mutations in non-small cell lung cancer (NSCLC) and the successful clinical application of EGFR tyrosine kinase inhibitors (TKIs) have changed the regimen of lung cancer therapy from traditional cytotoxic chemotherapy to molecular-targeted cancer therapy. However, the main limitation of EGFR-TKI therapy is the heterogeneity of lung cancer harboring EGFR-sensitive mutations. In addition, the synergistic effect of the administration of chemotherapy and EGFR-TKIs, combined with tumor heterogeneity, on NSCLC remains unclear. The present study aimed to investigate the optimal schedule for combined treatment with paclitaxel/gemcitabine and gefitinib in co-cultured NSCLC cell lines, in which PC9 cells were mixed with A549 cells at 0:1, 1:19, 1:3, 1:1, 3:1 and 1:0 ratios, and clarified the associated mechanisms. The mixed cells were used to simulate the tumor heterogeneity in the human cancer environment and to define the differential anti-proliferative effects of nine schedules of paclitaxel/gemcitabine and gefitinib, based on cell cycle distribution. We confirmed that gefitinib arrested PC9 cell growth, mainly at the G1 phase, at 24 h regardless of low or high concentration. After a 24-h culture in gefitinib-free medium, the cell cycle returned to its normal state. Paclitaxel and gemcitabine induced G2/M phase and S phase arrest at 72 h, respectively. The anti-proliferative effect of paclitaxel/gemcitabine followed by gefitinib resulted in the optimum anti-proliferative activity compared with the other seven schedules, which was not affected by tumor heterogeneity. Cell cycle-dependent synergism may contribute to this effect. Our results are in accordance with most of the existing clinical trials, and could provide a potential treatment option for patients with advanced NSCLC and for the ongoing clinical investigation of the sequential treatment of NSCLC.

• 出版日期2018-8
• 单位复旦大学