Inhibition MNK‐eIF4E‐β‐catenin preferentially sensitizes gastric cancer to chemotherapy

• Published in: Fundamental & clinical pharmacology 2022-08, Vol.36 (4), p.712-720
• Main Authors: Yang, Xiaolin, Liu, Zhenyang, Yin, Xianli, Zeng, Yidong, Guo, Geyang
• Format: Article
• Language: English
• Subjects: Cancer; Catenin; Chemotherapy; chemo‐sensitization; Clinical trials; Gastric cancer; Initiation factor eIF-4E; Kinases; MAP kinase; MNK‐eIF4E‐β‐catenin; Paclitaxel; Pharmacology; Phosphorylation; tomivosertib
• ISSN: 0767-3981; 1472-8206
• DOI: 10.1111/fcp.12759

Aberrant activation of eIF4E contributes to gastric cancer growth and resistance. MAPK‐interacting kinases (MNKs) regulate eIF4E phosphorylation and activity in tumor but not normal cells and are potentially safe targets for the treatment of various cancers. Our work reveals that tomivosertib, a potent and highly selective dual MNK1/2 inhibitor, preferentially sensitizes gastric cancer to chemotherapy via suppressing MNK‐eIF4E‐β‐catenin. We firstly demonstrate that tomivosertib displays higher efficacy than other MNK inhibitors in inhibiting gastric cancer cells. In addition, tomivosertib significantly augments the inhibitory effects of 5‐FU and paclitaxel but not everolimus, suggesting that tomivosertib preferentially sensitizes gastric cancer to chemotherapy. We next show that eIF4E overexpression and phosphorylation coordinately regulate β‐catenin signaling in gastric cancer. Rescue studies confirm that tomivosertib inhibits gastric cancer via targeting MNK‐ eIF4E‐β‐catenin. Finally, we demonstrate that the in vitro functional and mechanism observations are translatable to in vivo gastric cancer model in mice. Tomivosertib is now in Phase 2 clinical trials. Our study provides preclinical evidence to initialize clinical trials for gastric cancer using tomivosertib in combination with chemotherapy.