Zhan Yihong, Wang Yue, Qi Miao, Liang Panpan, Ma Yu, Li Ting, Li Hui, Dai Congmei, An Zhifeng, Qi Yitao, Wu Hongmei, Shao Huanjie
National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, College of Life Sciences, Shaanxi Normal University, Xi'an, 710119 Shaanxi China.
Cell Biosci. 2019 Jul 23;9:60. doi: 10.1186/s13578-019-0322-y. eCollection 2019.
Mutated epidermal growth factor receptor (EGFR) is one of the most successful targets in cancer targeted therapy. While this treatment has benefited many patients with an activating EGFR mutation (EGFRm), almost all those who initially benefited will eventually develop acquired drug resistance (ADR) after a certain period of time. New therapeutic strategies need to be explored to treat EGFRm tumors and overcome or minimize this recurring ADR.
Our data showed that apigenin alone has only mild inhibitory effects on EGFRm tumor cells. By drug screening, we found that ABT-263 can significantly enhance the antitumor activities of apigenin in tumor cells harbouring an activating EGFR mutation and AZD9291-resistant H1975 cells. Mechanistically, apigenin upregulated the expression of Noxa in EGFRm tumor cells by targeting the AKT-FoxO3a pathway, thereby synergizing with ABT-263 to suppress tumor cell growth and proliferation in vitro and in vivo.
Our study provides a rationale for the clinical application of the combination treatment of apigenin and BH3 mimetics in the treatment of EGFRm tumors.
突变型表皮生长因子受体（EGFR）是癌症靶向治疗中最成功的靶点之一。虽然这种治疗使许多携带激活型EGFR突变（EGFRm）的患者受益，但几乎所有最初受益的患者最终在一段时间后都会出现获得性耐药（ADR）。需要探索新的治疗策略来治疗EGFRm肿瘤并克服或尽量减少这种复发性ADR。
我们的数据表明，芹菜素单独对EGFRm肿瘤细胞只有轻微的抑制作用。通过药物筛选，我们发现ABT-263能显著增强芹菜素对携带激活型EGFR突变的肿瘤细胞和对AZD9291耐药的H1975细胞的抗肿瘤活性。从机制上讲，芹菜素通过靶向AKT-FoxO3a途径上调EGFRm肿瘤细胞中Noxa的表达，从而与ABT-263协同作用，在体外和体内抑制肿瘤细胞的生长和增殖。
我们的研究为芹菜素和BH3模拟物联合治疗EGFRm肿瘤的临床应用提供了理论依据。
