Inhibition of Eukaryotic Initiating Factor eIF4E Overcomes Abemaciclib Resistance in Gastric Cancer  

作　　者：Huo-long ZHA Wei CHEN Wei SHI Ying-ying LIAO 

机构地区：[1]Department of Gastroenterology,Renmin Hospital,Hubei University of Medicine,Shiyan 442000,China [2]Department of Critical Care Medicine,Taihe Hospital,Hubei University of Medicine,Shiyan 442000,China

出　　处：《Current Medical Science》2023年第5期927-934,共8页当代医学科学（英文）

基　　金：supported by the Nature Science Foundation of Hubei Province(No.2017CFB606).

摘　　要：Objective Aberrant activating mutations in cyclin-dependent kinases 4 and 6(CDK4/6)are common in various cancers,including gastroesophageal malignancies.Although CDK4/6 inhibitors,such as abemaciclib and palbociclib,have been approved for breast cancer treatment,their effectiveness as a monotherapy remains limited for gastroesophageal tumors.The present study explored the underlying mechanism of abemaciclib resistance.Methods Abemaciclib-resistant gastric cancer cell lines were generated,and the phospho-eukaryotic translation initiation factor 4E(p-eIF4E)and eIF4E expression was compared between resistant and parental cell lines.In order to analyze the role of eIF4E in cell resistance,siRNA knockdown was employed.The effectiveness of ribavirin alone and its combination with abemaciclib was evaluated in the gastric cancer xenograft mouse model.Results The upregulation of eIF4E was a common feature in gastric cancer cells exposed to prolonged abemaciclib treatment.Gastric cancer cells with increased eIF4E levels exhibited a better response to eIF4E inhibition,especially those that were resistant to abemaciclib.Ribavirin,which is an approved anti-viral drug,significantly improved the efficacy of abemaciclib,both in vitro and in vivo,by inhibiting eIF4E.Importantly,ribavirin effectively suppressed the abemaciclib-resistant gastric cancer growth in mice without causing toxicity.Conclusion These findings suggest that targeting eIF4E can enhance the abemaciclib treatment for gastric cancer,proposing the potential combination therapy of CDK4/6 inhibitors with ribavirin for advanced gastric cancer.

关 键 词：EIF4E CDK4/6 RIBAVIRIN gastric cancer RESISTANCE 

分 类 号：R735.2[医药卫生—肿瘤]