Basroparib inhibits YAP-driven cancers by stabilizing angiomotin

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Yes-associated protein (YAP) is a critical oncogene and a major cause of resistance to cancer therapies, particularly in KRAS-mutant tumors.
• Targeting YAP is clinically relevant, but direct inhibitors are scarce.
• Tankyrase (TNKS) inhibitors, like basroparib, suppress Wnt signaling and may offer an indirect approach to YAP inhibition.

Purpose of the Study:

• To investigate the efficacy of basroparib in attenuating YAP-driven oncogenic programs.
• To determine if basroparib can overcome resistance to MEK inhibitors in colorectal cancer (CRC).
• To explore basroparib's potential as a dual Wnt-YAP pathway inhibitor.

Main Methods:

• Treatment of colorectal cancer cells with basroparib.
• Assessment of angiomotin (AMOT) protein levels and AMOT-YAP complex formation.
• Analysis of YAP localization and YAP-dependent transcription.
• Evaluation of drug sensitivity to MEK inhibitors in YAP-overexpressing and MEK inhibitor-resistant CRC models.
• In vitro and in vivo studies in various YAP-active tumor models.

Main Results:

• Basroparib increased AMOT protein, promoted AMOT-YAP complex formation, and led to YAP cytoplasmic sequestration, reducing YAP transcription.
• Basroparib sensitized YAP-overexpressing, KRAS-mutant CRC cells to MEK inhibition.
• In MEK inhibitor-resistant CRC models, basroparib restored sensitivity to MEK inhibitors.
• The drug enhanced MEK inhibitor efficacy in other YAP-active tumors but not in YAP-inactive models.

Conclusions:

• Basroparib effectively inhibits YAP-driven oncogenic programs by stabilizing AMOT.
• Basroparib shows promise in overcoming therapeutic resistance in YAP-driven cancers, particularly KRAS-mutant CRC.
• Basroparib represents a potential therapeutic strategy for dual Wnt-YAP pathway blockade and warrants further clinical investigation (Phase I, NCT04505839).