Li Ling, Hu Mengdi, Wang Tao, Chen Hongzhuan, Xu Lu
Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Institute of Interdisciplinary Integrative Biomedical Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Front Oncol. 2020 Jan 14;9:1503. doi: 10.3389/fonc.2019.01503. eCollection 2019.
The major limitation of targeted cancer therapy is development of acquired resistance. Intratumoral heterogeneity and coexist of multiple resistance mechanisms make combination therapies targeting one specific mechanism inefficient. Transcriptional signature obtained from GEO was used to reposition FDA-approved drugs to treat lung and breast cancers as well as overcome acquired resistance to EGFR TKIs in lung cancer and to tamoxifen in breast cancer via CMap. and models were used to examine candidate drugs for their anti-cancer and anti-resistance efficacy and underlying mechanisms. We found that aspirin, the most commonly used drug, not only inhibited proliferation and promoted apoptosis of cancer cells, but also delayed and overcame acquired resistance to targeted therapy using and models. The underlying mechanism could be attributed to enhanced cancer stemness and activated NF-κB signaling in acquired resistant tumors, both of which were suppressed by aspirin and rendered resistant tumors more sensitive to aspirin. Our data identify aspirin as a potential candidate for combination therapy for lung and breast cancers.
靶向癌症治疗的主要局限性是获得性耐药的出现。肿瘤内的异质性和多种耐药机制的共存使得针对一种特定机制的联合疗法效率低下。从基因表达综合数据库（GEO）获得的转录特征被用于重新定位美国食品药品监督管理局（FDA）批准的药物，以治疗肺癌和乳腺癌，并通过连接图谱（CMap）克服肺癌对表皮生长因子受体酪氨酸激酶抑制剂（EGFR TKIs）以及乳腺癌对他莫昔芬的获得性耐药。利用细胞模型和动物模型来检测候选药物的抗癌和抗耐药疗效及其潜在机制。我们发现，最常用的药物阿司匹林不仅抑制癌细胞增殖并促进其凋亡，还利用细胞模型和动物模型延缓并克服了对靶向治疗的获得性耐药。其潜在机制可能归因于获得性耐药肿瘤中癌症干性增强和核因子κB（NF-κB）信号通路激活，而阿司匹林对二者均有抑制作用，从而使耐药肿瘤对阿司匹林更敏感。我们的数据表明阿司匹林是肺癌和乳腺癌联合治疗的潜在候选药物。
