Abstract 7280: Potential activity of TEAD inhibitor in Hippo-altered cancer including NF2 mutant solid cancer and TAZ-CAMTA1 fusion-driven epithelioid hemangioendothelioma (EHE)

Abstract

Abstract The Hippo pathway, a conserved signaling, modulates diverse processes including cell proliferation, survival, differentiation, organ size, and tissue homeostasis. The core kinases, MST1/2 and LATS1/2 phosphorylate downstream effectors, YAP/TAZ, and sequestrate them in cytoplasm1). The upstream regulator, NF2 activates these kinases and its loss-of-function mutation leads to YAP nuclear translocation, which in turn promotes tumorigenesis2). Dysregulation of Hippo pathway triggers constitutive YAP/TAZ accumulation and binding to TEAD family that upregulate prosurvival target genes such as CTGF and CYR611), which are deeply associated with drug resistance and tumor microenvironment3). TEADs, a transcription activation complex with primary key partners of YAP/TAZ, function in response to the Hippo altered-pathway4). Although a number of reports in the area of small molecules targeting YAP/TAZ-TEAD complex is exponentially increased, there is a lack of understanding regarding how TEAD subtypes may contribute to cancer progression. Moreover, TAZ-CAMTA1 gene fusion is a driver oncogene expressed in more than 90% of epithelioid hemangioendothelioma (EHE), a vascular sarcoma5). Here, we explore the potential of anti-cancer efficacy on our established TAZ-CAMTA1 fusion-driven EHE model. Our TEAD inhibitor effectively suppressed TEAD reporter activity in MCF7-TEAD-luc cells and induced 10~100 nM range of growth inhibition in NF2 or LATS mutant mesothelioma by disrupting YAP-TEAD1/3 protein-protein interactions (PPI). We found that knockdown TEAD1 as well as TEAD3 downregulate growth ability of NF2 altered solid cancer cells such as LOU-NH-91 and YD8. Our TEAD inhibitor, showing TEAD1/3 isoform specificity, exhibited a superior anti-proliferative effect in broader range of Hippo-altered solid cancer cells than of selective TEAD1 inhibitor. This highlights the importance of targeting TEAD1 and suggest that TEAD3 inhibition can enhance anticancer effects. We established the TAZ-CAMTA1 fusion-expressing cells, demonstrating its oncogenic function through increased anchorage-independent growth and upregulation of TEAD target genes, CTGF and CYR61, compared to parental NIH3T3. Our TEAD inhibitor suppressed TAZ-CAMTA1 fusion-TEAD1 PPI in NanoBRET system. It also inhibited TAZ-CAMTA1 driven colony formation. Our inhibitor more greatly prevented the growth of TAZ-CAMTA1 expressing NIH3T3 cells than parental cells and exhibited mRNA expression inhibition of CTGF and CYR61 on qRT-PCR, showing superior effects compared to the selective TEAD1 inhibitor. In conclusion, we emphasize the importance of TEAD inhibition for the treatment of Hippo-altered cancers including NF2 mutant solid cancer and TAZ-CAMTA1 fusion-driven EHE, highlighting the advantages of our TEAD1/3 inhibitor over the selective TEAD1 inhibitor. Citation Format: Jooyun Byun, Seung Hyun Jung, Heesun Moon, Semi Lim, Soonki Park, Seungheon Baek, Yu-Yon Kim, Junghwa Park, Jisook Kim, Sang Hyun Lee, Young Gil Ahn. Potential activity of TEAD inhibitor in Hippo-altered cancer including NF2 mutant solid cancer and TAZ-CAMTA1 fusion-driven epithelioid hemangioendothelioma (EHE) [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 7280.