Abstract 4516: Inhibiting YAP activity in cancers by targeted degradation of TEAD

Abstract

Abstract The oncogenic transcriptional coactivators YAP/TAZ function as the terminal effectors of the Hippo signaling pathway and are dysregulated in many human cancers, where they promote cancer cell proliferation, survival, stemness, and resistance to targeted therapies, and thus provide a critical point for therapeutic targeting. YAP/TAZ activity is regulated by phosphorylation mediated by the kinase cascade of the Hippo signaling pathway, where phosphorylation causes cytoplasmic retention. Aberrantly activated Hypo/unphosphorylated YAP/TAZ translocates into the nucleus, where it exerts its oncogenic activity by associating with the TEAD1-4 transcription factors and inducing expression of genes encoding pro-proliferative and antiapoptotic factors. Since YAP/TAZ cannot be directly therapeutically targeted, its oncogenic transcriptional activity can be controlled indirectly by targeted degradation of TEAD. Here we report on the development of Proteolysis Targeting Chimeras that potently induces degradation of TEAD and inhibits YAP transcriptional activity and cell proliferation in YAP-dependent cancers. Citation Format: Hui Chen, Artem Gridnev, Netanya Schlamowitz, Guangrong Zheng, Jyoti R. Misra. Inhibiting YAP activity in cancers by targeted degradation of TEAD [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4516.