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

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Aberrant eukaryotic initiation factor 4E (eIF4E) activation drives gastric cancer progression and chemoresistance.
• Mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) modulate eIF4E activity in cancer cells, presenting them as potential therapeutic targets.

Purpose of the Study:

• To investigate the efficacy of tomivosertib, a dual MNK1/2 inhibitor, in sensitizing gastric cancer to chemotherapy.
• To elucidate the underlying molecular mechanism involving the MNK-eIF4E-β-catenin signaling pathway.

Main Methods:

• In vitro assays assessing gastric cancer cell viability and drug synergy.
• Western blotting and rescue experiments to confirm pathway involvement.
• In vivo studies using a murine gastric cancer model.

Main Results:

• Tomivosertib demonstrated superior efficacy in inhibiting gastric cancer cells compared to other MNK inhibitors.
• Tomivosertib significantly enhanced the effects of 5-FU and paclitaxel chemotherapy, but not everolimus.
• The drug's mechanism involves suppressing the MNK-eIF4E-β-catenin signaling axis, confirmed by rescue studies.
• Preclinical findings translated to efficacy in an in vivo gastric cancer model.

Conclusions:

• Tomivosertib effectively sensitizes gastric cancer to specific chemotherapies by targeting the MNK-eIF4E-β-catenin pathway.
• These preclinical findings support initiating Phase 2 clinical trials combining tomivosertib with chemotherapy for gastric cancer treatment.