Abstract 5364: The TEAD autopalmitoylation inhibitor VT3989 improves efficacy and increases durability of efficacy of osimertinib in preclinical EGFR mutant tumor models

Abstract

Abstract The Hippo-YAP/TAZ pathway is involved in the regulation of cell proliferation, survival, and cell migration. The major effectors of the Hippo pathway are the TEAD transcription factors, which become transcriptionally activated upon YAP/TAZ binding. Genetic alterations of pathway components have been reported in a variety of human malignancies, resulting in YAP/TAZ constitutive nuclear localization and TEAD activation. The TEAD transcription factors have been shown to autopalmitoylate, and palmitoylation is required for its interaction with YAP/TAZ and hence activation of transcriptional activity. We have identified potent, selective, and orally available small molecule compounds that directly interact with TEAD and block its autopalmitoylation (Tang et al, 2021, Mol Cancer Ther. 20(6):986-998). These TEAD inhibitors disrupt YAP/TAZ-TEAD protein interaction, suppress TEAD transcriptional activity, and selectively block proliferation of NF2-deficient mesothelioma in vitro and inhibit NF2 mutant xenograft tumor growth in vivo. Nuclear YAP accumulation and functional requirement have also been linked to resistance to targeted therapies and cancer relapse in BRAF-mutant, KRAS-mutant, EGFR-mutant, and ALK-rearranged non-small cell lung cancers (NSCLC). Hence, as TEAD transcription factors are the main drivers for YAP/TAZ recruitment to chromatin, we evaluated the effect of our TEAD inhibitor VT3989, currently in clinical testing, on emerging drug tolerant persistent cancer cells and drug resistance during EGFR-tyrosine kinase inhibitor osimertinib treatment in combination studies. In in vitro cell proliferation assays, VT3989 showed strong to very strong synergy in combination with osimertinib in several EGFR mutant NSCLC cell lines tested. In vivo, we observed strong VT3989 and osimertinib combination effect in NCI-H1975 and HCC827 cell line-derived xenograft models. We also tested the combination in several EGFR mutant NSCLC patient-derived xenograft models and demonstrated that the addition of VT3989 enhanced the efficacy of osimertinib and delayed tumor regrowth compared to osimertinib alone. Citation Format: Tracy T. Tang, Leonard Post. The TEAD autopalmitoylation inhibitor VT3989 improves efficacy and increases durability of efficacy of osimertinib in preclinical EGFR mutant tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5364.