Abstract 5635: In vivo assessment of a potent TEAD inhibitor in a panel of malignant mesothelioma PDX model

Abstract There has been a growing interest in understanding the involvement of the HIPPO tumor suppressor pathway and its downstream effector, Yes1-associated transcriptional regulator (YAP1), in the context of cancer. The YAP1-TEAD complex plays a pivotal role in controlling transcription, influencing cell proliferation, survival, adaptability, and cell migration. Abnormal activation of YAP1 has been documented in various cancer types, including Malignant Mesothelioma (MM). To assess the proportion of MM cases in which YAP1/TEAD-dependent transcription contributes to tumor initiation and progression and to evaluate the pharmacodynamic effects of a new TEAD inhibitor (Compound A), we previously established a gene expression signature associated with YAP1 activity. This signature was employed to monitor the level of YAP1 inhibition in three Cell Line Derived Xenografts (CDX) and eight Patient Derived Xenografts (PDX) of malignant mesothelioma, and it was used to further assess the effectiveness of compound A in vivo. Here we present, for the first time, the potent in vivo antitumor properties of the novel TEAD inhibitor, compound A, in all of these models and we confirm the reliability of the YAP1-transcription signature as a biomarker for patient selection and for assessing the pharmacodynamic effects of YAP1-TEAD inhibition. Citation Format: Loreley Calvet, Odette Dos-Santos, Emmanuel Spanakis, Anne Caron, Laurence Noblet, Isabelle Sanchez, Yvette Ruffin, Laurent Dassencourt, Philipe Prigent, David Machnik, Olivier Venier, Laurent Debussche, Iris Valtingojer, Valeria Fantin, Sukhvinder Sidhu. In vivo assessment of a potent TEAD inhibitor in a panel of malignant mesothelioma PDX model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5635.