Journal Article

An allosteric pan-TEAD inhibitor blocks oncogenic YAP/TAZ signaling and overcomes KRAS G12C inhibitor resistance

Arrazate, Alfonso, Levy, Elizabeth, Modrusan, Zora, Ye, Xin, Fong, Rina, Chan, Emily, Hafner, Marc, Maddalo, Danilo, Martin, Scott, Steffek, Micah, Kubala, Marta H., Lorenzo, Maria N., Lau, Jeffrey T., Lee, Ho-June, Zang, Richard, Schmidt, Stephen, Lacap, Jennifer A., Kabza, Michal, Pham, Trang H., Beroza, Paul, Sodir, Nicole M., Lin, Eva, Zbieg, Jason R., An, Le, Evangelista, Marie, Ahmed, Musaddeque, Kishore, Ayush, Afghani, Shervin, Bhat, Kamakoti P., Yao, Xiaosai, Chang, Matthew T., Yang, Michelle N.-Y., Hagenbeek, Thijs J., Clausen, Saundra, Crawford, James J., Chen, Yi-Chen, Li, Jason, Noland, Cameron L., Di Lello, Paola, Dey, Anwesha, Mroue, Rana, Lee, Wendy

2023

Overview

The Hippo pathway is a key growth control pathway that is conserved across species. The downstream effectors of the Hippo pathway, YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), are frequently activated in cancers to drive proliferation and survival. Based on the premise that sustained interactions between YAP/TAZ and TEADs (transcriptional enhanced associate domain) are central to their transcriptional activities, we discovered a potent small-molecule inhibitor (SMI), GNE-7883, that allosterically blocks the interactions between YAP/TAZ and all human TEAD paralogs through binding to the TEAD lipid pocket. GNE-7883 effectively reduces chromatin accessibility specifically at TEAD motifs, suppresses cell proliferation in a variety of cell line models and achieves strong antitumor efficacy in vivo. Furthermore, we uncovered that GNE-7883 effectively overcomes both intrinsic and acquired resistance to KRAS (Kirsten rat sarcoma viral oncogene homolog) G12C inhibitors in diverse preclinical models through the inhibition of YAP/TAZ activation. Taken together, this work demonstrates the activities of TEAD SMIs in YAP/TAZ-dependent cancers and highlights their potential broad applications in precision oncology and therapy resistance.

• Publisher: Nature Publishing Group,Nature Publishing Group US
• Subject: Cancer therapies / Crystal structure / Cyclin-dependent kinases / Humans / Hydrogen bonds / Kinases / Lipids / Neoplasms / Peptides / Precision Medicine / Proteins / Proto-Oncogene Proteins p21(ras) - genetics / Signal Transduction / Transcription Factors - metabolism / Tumors