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

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 lenvatinib, resulting in increased antitumor efficacy. Upregulation of ATF4 gene expression signatures was confirmed in four of seven E7386 + lenvatinib-treated patients with HCC, three of whom exhibited tumor diameter shrinkage >30%. CONCLUSIONS: E7386 sensitized tumors to lenvatinib, thereby enhancing survival in mice compared with either monotherapy. In patients, E7386 combined with lenvatinib promoted tumor shrinkage and, in parallel, activated ATF4 signaling.