Abstract 5362: Molecular profiling of SW-682, a pan-TEAD inhibitor, as monotherapy and in combination with other treatments across tumor types

Abstract Hyperactivation of YAP/TAZ signaling (Hippo pathway) can drive oncogenesis across multiple cancer types by binding to the transcription factor TEAD and driving expression of target genes involved in cell proliferation and tumor progression. SW-682, an investigational pan-TEAD small molecule inhibitor, blocks TEAD-dependent transcription by binding to the palmitoylation pocket of all TEAD paralogs. We have previously demonstrated monotherapy efficacy of SW-682 in in vivo models of mesothelioma and head and neck squamous cell carcinoma (HNSCC) harboring Hippo pathway genomic alterations. We have also reported significant benefit of SW-682 in combination with KRAS G12C inhibitor, sotorasib, in KRAS G12C non-small cell lung cancer (NSCLC) models. Here, we sought to characterize the molecular signature of HNSCC, mesothelioma, and NSCLC tumors after TEAD inhibition either with SW-682 alone or in combination with KRAS G12C inhibitors. To identify downstream targets of TEAD inhibition and compare them with other known Hippo pathway signatures, we performed RNA-seq analysis of tumors following SW-682 monotherapy in mesothelioma and HNSCC CDX (cell-line-derived xenograft) models. We identified TEAD-dependent transcriptional changes for each model that included significant overlap with published YAP/TAZ gene signatures. Additionally, we compared our data with publicly available preclinical RNA-seq data generated with other TEAD inhibitors. To account for experimental variability across datasets, the analysis was divided longitudinally into early (<6 hour) and late (>24 hour) timepoints for each disease model. This meta-analysis confirmed genes identified from RNA-seq and revealed complexities in identifying a universal TEAD-dependent gene signature. Since hyperactivated YAP/TAZ signaling is also known to be a common resistance mechanism to targeted therapies, we assessed the relationship between dysregulated Hippo signaling and responses to SW-682 and sotorasib combination in a panel of KRAS G12C NSCLC xenograft models. We observed combination benefits more frequently in xenograft models with elevated tumor intrinsic YAP/TAZ activity. However, Hippo pathway gene alterations alone were not sufficient to predict sensitivity to combination of SW-682 and sotorasib. Therefore, we sought to characterize molecular signatures that correlated with combination benefits by analyzing baseline DNA mutation status and RNA expression levels in each model. In conclusion, these results help elucidate SW-682 molecular signatures across different tumor types and can support combination strategies for SW-682 in clinical investigation. Supported by SpringWorks Therapeutics, Inc. Citation Format: Somdutta Saha, Veronica Jové, Amelia Schirmer, Lorne Celentano, Alma Chanelo, Connor Smith, Sarah Ahn, Jim Smothers, Wenlin Shao, Tai-An Lin, Paula Miliani de Marval, Lei Chen, Robert Dubose. Molecular profiling of SW-682, a pan-TEAD inhibitor, as monotherapy and in combination with other treatments across tumor types [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 5362.