Abstract 3047: Interrogating TEAD protein interactions in cancer

Abstract The Hippo signaling pathway is a major regulator of cellular growth and is frequently deregulated in cancer. The main effectors of the Hippo pathway are the TEAD transcription factors which function by interacting with other co-effector proteins to modulate transcriptional outputs. Notably YAP and TAZ interact with TEAD to mediate oncogenic transcriptional programs, and blocking interaction of TEAD with YAP and TAZ is a sought-after mechanism for small molecule TEAD inhibitors. However, the interaction network of TEAD extends well beyond YAP and TAZ to a variety of additional cofactors, including chromatin remodelers, epigenetic factors, and other transcriptional regulators. Thus, the impact of inhibiting TEAD could extend to unanticipated protein interactions and cellular functions. The purpose of this study is to investigate, define, and interrogate TEAD interaction networks, providing foundational knowledge for interrogating TEAD biological functions and pharmacological effects. We are employing mass spectrometry-based technologies combined with chemical and genetic tools and biochemistry to interrogate TEAD protein interaction networks. We have performed affinity purification coupled with mass spectrometry for TEAD and have identified dozens of significant interacting proteins. TEAD interactions include expected proteins, such as known Hippo pathway members, as well as unexpected protein interactions, such as DNA damage response proteins. Cellular assays probing these DNA damage protein interactions implicate TEAD as a crucial factor for efficient DNA repair mechanisms and maintaining genomic stability. These results raise questions towards a combinatorial effect for TEAD inhibitors and DNA damaging chemotherapeutic agents. Altogether, these ongoing proteomic studies are providing insights into TEAD interaction networks, leading to a deeper understanding of TEAD biology, and providing foundational knowledge that can inform the development of TEAD inhibitors as effective cancer therapies. Citation Format: Alissa Guarnaccia, Jennie Lill, Anwesha Dey. Interrogating TEAD protein interactions in cancer 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 (6Suppl): Abstract nr 3047.