YAP/TAZ Score Predicts TEAD Inhibitor Sensitivity Beyond Hippo Alterations

YAP and TAZ are Hippo pathway effectors that bind TEAD transcription factors to drive oncogenic programs. First-in-human trials of TEAD inhibitors (TEADis) showed activity and tolerability in pretreated mesothelioma patients, yet current trials focus on mesotheliomas and rare Hippo-altered tumors, despite the broad oncogenic role of YAP/TAZ in various solid cancers. Whether YAP/TAZ target gene signatures can identify tumors with high YAP/TAZ activity and potential TEADi sensitivity beyond these indications remains unclear. We profiled YAP/TAZ activity using a 22-gene signature across 2390 advanced pediatric and 3746 advanced rare cancers or cancers from young adults (<51y) from the INFORM and DKFZ/NCT/DKTK MASTER (MASTER) trials. Benchmarking against mesothelioma and YAP fusion-driven ependymoma revealed subsets of cancers across entity baskets with equal or higher YAP/TAZ activity independent of Hippo alterations. To dissect tumor-intrinsic versus stromal contributions, we performed spatial transcriptomics on MASTER samples using microarrays and the Xenium platform (n=106 cores from 89 tumors representing >70 histological subtypes). Tumor-cell YAP/TAZ scores correlated strongly with bulk scores (r=0.61), whereas fibroblast (r=0.23) and immune-cell (r=0.35) correlations were weak, indicating that bulk scores largely reflect tumor-cell activity. We highlight a MASTER patient with MET-amplified carcinoma in whom progression on the MET inhibitor capmatinib coincided with a marked YAP/TAZ-score increase. In MET-amplified HS746T gastric cancer cells, genetic YAP/TAZ activation reduced capmatinib sensitivity, partially reversed by TEAD inhibition, supporting an unrecognized YAP/TAZ-linked resistance mechanism. To evaluate predictive capacity of the YAP/TAZ signature, 23 cancer cell lines and 30 patient-derived spheroid cultures (PDSCs) were treated with IAG933 (Ω-loop-binding TEADi) or VT107 (TEAD autopalmitoylation inhibitor). Across compounds and models, expression of genes most strongly associated with TEADi response were enriched for YAP/TAZ targets, enabling refinement of a TEADi response signature. This refined signature correlated with area-under-the-drug-response-curve (AUC) values (IAG933: Pearson r=0.81 for cell lines, r=0.60 for PDSCs; VT107: r=0.46 and r=0.45). Notably, the refined signature derived from INFORM/MASTER tumors predicted TEADi response in matched PDSCs (n=13; r=0.70 for IAG933, r=0.72 for VT107), with IC50 values as low as 30 nM. Sensitive PDSCs included atypical rhabdoid tumor, colorectal, and pancreatic carcinoma - all lacking Hippo alterations and representing entities not typically considered YAP/TAZ-driven. In summary, these data provide a strong rationale for a transcription-based stratified clinical trial evaluating TEAD inhibition across pediatric and adult advanced cancers irrespective of Hippo alterations. Citation Format: Michael Wegert-Verhoeven, Mathea Fransisca, Sylvia Martin, Attila Jady, Daniela Richter, Malgorzata Oles, Timon A. Blindauer, Jan-Philipp Mallm, Jasmina Paluncic, Claudia Dagostino, Olga Ermakova, Annika Schneider, Matthew The, Annika Baude-Müller, Katja Beck, Maximilian Bullemer, Victor Didier Meza, Vivek Venkataramani, Ralf C. Bargou, Heiko Becker, Melanie Boerries, Armin Tuchscherer, DKFZ/NCT/DKTK MASTER consortium, Martin Wermke, Andreas Brunschweiger, Mohammed Al-Saeedi, Dirk Jäger, Olaf Witt, Denis Schapiro, Bernhard Küster, Andreas Hartig, Michael Allgaeuer, Alexander Brobeil, Christoph E. Heilig, Maria Veronica Teleanu, Simon Kreutzfeldt, Peter Horak, Daniel Hübschmann, Wolfgang Hartmann, Marcel Trautmann, Ina Oehme, Claudia R. Ball, Stefan Fröhling, Stefan M. Pfister, Hanno Glimm, Sebastian M. Dieter. A tumor-agnostic YAP/TAZ score predicts TEAD inhibitor sensitivity independent of Hippo alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1028.