Inhibition of the YAP-MMB interaction and targeting NEK2 as potential therapeutic strategies for YAP-driven cancers

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• YAP activation is a key driver in various cancers, correlating with poor patient prognosis.
• Targeting YAP-TEAD interactions has been a primary strategy, but alternative pathways are being explored.

Purpose of the Study:

• To investigate the therapeutic potential of disrupting the YAP-B-MYB protein-protein interaction.
• To evaluate the efficacy of MY-COMP, a novel peptide inhibitor, in cancer models.

Main Methods:

• Utilized MY-COMP, a B-MYB fragment designed to inhibit YAP binding.
• Assessed MY-COMP's effects on cell cycle, nuclear morphology, and polyploidization in cancer cell lines.
• Tested MY-COMP in an AKT and YAP-driven mouse model of liver cancer and in YAP-dependent/independent melanoma cell lines.

Main Results:

• MY-COMP induced significant cell cycle defects, nuclear abnormalities, and polyploidization.
• In a liver cancer model, MY-COMP markedly reduced tumor development.
• MY-COMP selectively affected YAP-dependent uveal melanoma cells, not YAP-independent cutaneous melanoma cells.
• The compound counteracted YAP-dependent gene expression involved in cell cycle regulation.
• NIMA-related kinase 2 (NEK2) was identified as a downstream target promoting YAP-driven transformation.

Conclusions:

• The YAP-B-MYB interaction is crucial for tumor development, particularly in YAP-driven cancers.
• MY-COMP represents a potential therapeutic strategy by targeting this interaction.
• NEK2 plays a role in YAP-driven transformation through effects on centrosome dynamics.