Inhibition of eukaryotic initiation factor 4E by tomivosertib suppresses angiogenesis, growth, and survival of glioblastoma and enhances chemotherapy's efficacy

Abstract

AbstractGlioblastoma is characterized by extensive vascularization and is highly resistant to current therapy. Identification of drugs that target tumor directly and angiogenesis processes present an effective therapeutic strategy for glioblastoma. Mnk kinase is required for the activation of eukaryotic initiation factor 4E (eIF4E), which mediates translation of oncogenic proteins. We investigated the effects of tomivosertib, a novel MAPK‐interacting kinase (MNK) inhibitor, on glioblastoma angiogenesis, growth, and survival. We found that tomivosertib inhibited growth and induced caspase‐dependent apoptosis in various glioblastoma cell lines. Tomivosertib disrupted glioblastoma endothelial cell capillary network formation, growth, and survival. Mechanistically, tomivosertib acted on glioblastoma via suppressing MNK‐dependent eIF4E phosphorylation and activation in tumor and endothelial cells. We further found that temozolomide activated eIF4E and this was reversed by tomivosertib. Using glioblastoma xenograft mouse model, we demonstrated that temozolomide and tomivosertib combination had higher efficacy than tomivosertib alone. Of note, tomivosertib inhibited glioblastoma angiogenesis and decreased p‐eIF4E level in mice. We finally showed that p‐eIF4E activation was a common molecular feature in glioblastoma patients. Our pre‐clinical findings suggest that tomivosertib is a useful addition to the treatment armamentarium for glioblastoma and that targeting MNK‐eIF4E pathway represents a therapeutic strategy to overcome glioblastoma chemoresistance.