E7386 Enhances Lenvatinib’s Antitumor Activity in Preclinical Models and Human Hepatocellular Carcinoma

作者：Agavni Mesropian, Albert Gris‐Oliver, Ugne Balaseviciute, Alka A. Potdar, Takayuki Kimura, Jialing Shen, Martí Torres-Marcén, Jordi Abril‐Fornaguera, Marta Piqué‐Gili, David Camell-Raventos, Judit Peix, Elisa Fernández‐Martínez, Júlia Huguet‐Pradell, Ana Hernández de Sande, Ieva Keraite, Roger Esteban-Fabró, Marina Bárcena‐Varela, Katherine E. Lindblad, Amaia Lujambio, Ernesto Guccione, Swan N. Thung, Masafumi Ikeda, Masatoshi Kudo, Daniela Sia, Roser Pinyol, Josep M. Llovet · 发表于：Clinical Cancer Research · 年份：2025 · DOI：10.1158/1078-0432.ccr-25-0725 · 被引用次数：8 · 研究领域：Wnt/β-catenin signaling in development and cancer、Kruppel-like factors research、Heat shock proteins research

PURPOSE: Aberrant activation of β-catenin (CTNNB1) occurs in ∼30% of hepatocellular carcinomas (HCC) and is associated with immune evasion and limited response to immunotherapy. However, it remains an undruggable target. In this study, we studied the antitumor and antiangiogenic activity of combining E7386 [an oral protein-protein interaction inhibitor targeting CREB-binding protein (CBP)/β-catenin] with lenvatinib and elucidated a novel mechanism of action of E7386 that boosts the antitumor response. EXPERIMENTAL DESIGN: We generated a genetically engineered CTNNB1-mutant murine HCC model and randomized the animals to receive vehicle, E7386, lenvatinib, or the combination (n = 22-23/arm). We evaluated survival and analyzed the tumors transcriptomically and by IHC. Also, we analyzed five patient-derived organoids, four HCC cell lines, and seven paired pre-/on-treatment specimens from patients with HCC receiving E7386 in combination with lenvatinib in the context of a phase Ib/II trial (NCT04008797). RESULTS: E7386 in combination with lenvatinib significantly prolonged mouse survival compared with monotherapy. Cell lines and patient-derived organoid data corroborated that sensitivity to E7386 involves processes beyond CBP/β-catenin interaction blockade. Mechanistically, E7386 promoted activating transcription factor 4 (ATF4) activation, triggering the integrated stress response in preclinical models of HCC. In vivo, E7386 concomitantly potentiated the antiangiogenic effects of...