Cotargeting MNK and MEK kinases induces the regression of NF1-mutant cancers

Area of Science:

• Oncology
• Molecular Biology
• Cancer Signaling Pathways

Background:

• Neurofibromin 1-mutant (NF1-mutant) cancers exhibit excessive Ras signaling, lacking effective targeted therapies.
• Combined MEK and mTORC1 suppression shows efficacy in preclinical models but raises toxicity concerns.
• Identifying refined, cancer-specific targets is crucial for NF1-mutant malignancies.

Purpose of the Study:

• To investigate MAPK-interacting kinases (MNKs) as potential therapeutic targets in NF1-mutant cancers.
• To evaluate the efficacy of combined MNK and MEK inhibition in NF1-deficient tumor models.
• To explore the role of MNKs and eIF4E in the response to cabozantinib and MEK inhibitors.

Main Methods:

• Analysis of primary human NF1-deficient peripheral nervous system tumors for MNK activation.
• Genetic and chemical suppression of MNKs in NF1-deficient murine tumor models and human cell lines.
• Assessment of combination therapy with MEK inhibitors and cabozantinib in a genetically engineered tumor model.

Main Results:

• MNKs were found to be activated in the majority of tested human NF1-deficient tumors.
• Suppression of MNKs synergized with MEK inhibitors to eliminate NF1-deficient cancers via eIF4E.
• Cabozantinib was identified as a direct inhibitor of MNK kinases, and its combination with MEK inhibitors induced significant tumor regression.

Conclusions:

• Combined MNK and MEK suppression is a promising therapeutic strategy for Ras-driven NF1-mutant tumors.
• MNK inhibition, particularly through agents like cabozantinib, offers a targeted approach for these cancers.
• Development of selective MNK inhibitors could benefit NF1-mutant and other malignancies.