First-in-class YAP/TEAD Inhibitor Shows Promise in Hippo-driven Mesothelioma

The Hippo–YAP/TAZ–TEAD pathway regulates tissue growth, and its aberrant activation drives cancers such as mesothelioma, sarcoma, and meningioma. Loss of the upstream regulator NF2 (Merlin) causes constitutive TEAD activation and tumor proliferation. Despite its central role in tumorigenesis, no targeted therapies against this pathway have been approved. VT3989, a first-in-class oral TEAD autopalmitoylation inhibitor, blocks YAP-dependent transcriptional activity. In preclinical models, VT3989 selectively suppressed the growth of NF2-mutant or NF2-deficient mesothelioma cells and inhibited the growth of tumor xenograft models, highlighting a promising strategy to target Hippo pathway–driven cancers. Following these preclinical findings, Yap and colleagues launched a multicenter phase I/II clinical trial of VT3989 in patients with mesothelioma, meningioma, epithelioid hemangioendothelioma, or advanced sarcoma, refractory to standard therapies (NCT04665206). This study, which is ongoing, enrolled from March 2021 to March 2025 a total of 172 patients aged 21–88 years, most of whom had previously been treated with platinum chemotherapy and immunotherapy. The results of the dose escalation cohort (n = 85) established 100 mg daily on a 2-weeks-on/2-weeks-off schedule as the optimal regimen balancing safety and efficacy. VT3989 showed a favorable safety profile, with mostly low-grade proteinuria, edema, nausea, and fatigue. Among patients with mesothelioma treated at clinically optimized doses, the overall response rate (ORR) was 26–32%, disease control rate was 86%, and median progression-free survival was 10 months, suggesting clinical activity. Tumor biopsies obtained before and during treatment were analyzed by NanoString, revealing that VT3989 modulated multiple YAP/TAZ transcriptional targets, including CCN1, VEGFA, SOD2, and IL6. A Merlin–YAP duplex immunohistochemistry assay showed that most mesothelioma tumors exhibited low or absent Merlin expression. Among 11 patients with Merlin expression data, the ORR was 0% in Merlin-positive tumors versus 28.6% in Merlin-negative tumors. Consistent with preclinical findings, these results suggest that VT3989 antitumor activity is enriched in mesotheliomas with low Merlin expression, providing the first clinical proof-of-concept for effectively targeting the Hippo–YAP–TEAD pathway. VT3989 has since received orphan drug and fast-track designation from the U.S. Food and Drug Administration for the treatment of mesothelioma.Yap TA, Kwiatkowski DJ, Dagogo-Jack I, Offin M, Zauderer MG, Kratzke R, et al. YAP/TEAD inhibitor VT3989 in solid tumors: a phase 1/2 trial. Nat Med 2025 Oct 19 [Epub ahead of print].Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.