Abstract B088: VT3989, the first-in-class and first-in-human TEAD auto-palmitoylation inhibitor, enhances the efficacy and durability of multiple targeted therapies of the MAPK and P13K/AKT/mTOR pathways

Abstract TEAD transcription factors are the major effectors of the Hippo-YAP/TAZ-TEAD pathway involved in the regulation of cell proliferation, survival, and cell migration. TEAD auto-palmitoylation has been shown to be required for TEAD interaction with coactivator YAP/TAZ and hence activation of transcriptional activity. There are multiple reports that YAP/TEAD activation provides the essential survival signal in drug-tolerant persister/dormant cells in cancer in response to treatment with targeted therapies, leading to drug resistance and cancer relapse in BRAF-mutant, KRAS-mutant, EGFR-mutant, and ALK-rearranged non–small cell lung cancers (NSCLC). The TEAD inhibitor VT3989, currently in clinical testing, was evaluated for effect on emerging drug tolerant persister/dominant cancer cells and drug resistance. VT3989, with similar biological activity in vitro and in vivo as the potent small molecule TEAD auto-palmitoylation inhibitors reported (Tang et al, 2021, Mol Cancer Ther. 20(6):986-998), disrupts YAP/TAZ-TEAD protein interaction, suppresses TEAD transcriptional activity, and selectively blocks proliferation of NF2-deficient mesothelioma in vitro and inhibit NF2 mutant xenograft tumor growth in vivo. In in vitro assays as well as in vivo studies using cell line derived (CDX) and patient derived (PDX) xenograft models, VT3989 enhanced the efficacy and durability of clinically approved EGFR inhibitors (osimertinib, lazertinib), MET inhibitors (savolitinib, capmatinib), EGFR-MET bispecific antibody (amivantinib), KRAS-G12C inhibitors (sotorasib, adagrasib), BRAF inhibitors (encorafenib, dabrafenib), MEK inhibitors (trametinib, cobimetinib), and mTORC inhibitor (everolimus). With the addition of VT3989, combination anti-tumor effect was observed and/or tumor regrowth was delayed compared to monotherapy alone. Therefore, in addition to Hippo-YAP/TAZ-TEAD pathway driven cancers, such as mesothelioma, where VT3989 can show monotherapy efficacy, future VT3989 clinical studies will include combination therapy with approved targeted therapies to enhance the efficacy and durability of treatment. Citation Format: Tracy T Tang, Leonard Post. VT3989, the first-in-class and first-in-human TEAD auto-palmitoylation inhibitor, enhances the efficacy and durability of multiple targeted therapies of the MAPK and P13K/AKT/mTOR pathways [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B088.