Cyclopeptide RA-V Inhibits Organ Enlargement and Tumorigenesis Induced by YAP Activation

Area of Science:

• Oncology
• Molecular Biology
• Developmental Biology

Background:

• The Hippo pathway regulates organ size; its inactivation is linked to cancer.
• Yes-associated protein (YAP) and TAZ are key effectors of the Hippo pathway, promoting organ enlargement and tumor growth when the pathway is inactivated.
• Genetic YAP inactivation shows potential for inhibiting tumorigenesis.

Purpose of the Study:

• To identify pharmacological inhibitors of YAP.
• To evaluate the potential of identified inhibitors as cancer therapeutics.

Main Methods:

• Screened 52,683 compounds using a YAP-specific reporter assay.
• Tested identified inhibitor RA-V (deoxybouvardin) for its effects on YAP/TAZ, target gene expression, liver enlargement, and tumor growth in preclinical models.
• Assessed RA-V's impact on hepatocyte and macrophage proliferation, apoptosis, and differentiation.

Main Results:

• Identified cyclopeptide RA-V as a specific inhibitor of YAP and TAZ.
• RA-V repressed YAP target gene protein levels but not mRNA.
• RA-V blocked liver enlargement, inhibited YAP-induced liver tumorigenesis, and induced regression of established tumors.
• RA-V inhibited hepatocyte dedifferentiation and proliferation while inducing apoptosis; it also induced apoptosis and inhibited proliferation of tumor-associated macrophages.

Conclusions:

• RA-V is a specific inhibitor of YAP/TAZ.
• RA-V demonstrates therapeutic potential for YAP/TAZ-driven cancers by inhibiting tumor growth and inducing regression.
• RA-V impacts both tumor cells and the tumor microenvironment, making it a promising drug candidate for YAP/TAZ-activated cancers.