E7386 Enhances Lenvatinib's Antitumor Activity in Preclinical Models and Human Hepatocellular Carcinoma
Agavni Mesropian1,2,3, Albert Gris-Oliver1,2, Ugne Balaseviciute1,2,3
1Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.
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.
Insights
Combining E7386 with lenvatinib significantly improves survival in hepatocellular carcinoma (HCC) models by activating ATF4 signaling and enhancing antiangiogenic effects. This combination therapy shows promise for treating HCC patients, leading to tumor shrinkage.
Area of Science:
- Hepatocellular Carcinoma Research
- Drug Development
- Cancer Signaling Pathways
Background:
- Aberrant β-catenin (CTNNB1) activation in ~30% of HCCs is linked to immune evasion and poor immunotherapy response.
- CTNNB1 remains an undruggable target in HCC treatment.
- Novel therapeutic strategies are needed to overcome resistance in HCC.
Purpose of the Study:
- To evaluate the antitumor and antiangiogenic activity of combining E7386 (a CBP/β-catenin inhibitor) with lenvatinib.
- To elucidate the novel mechanism of action of E7386 in boosting antitumor response.
- To assess the efficacy of this combination in preclinical HCC models and patient samples.
Main Methods:
- Generated a genetically engineered CTNNB1-mutant murine HCC model.
- Randomized mice to vehicle, E7386, lenvatinib, or combination therapy.
- Analyzed survival, tumor transcriptomics, IHC, patient-derived organoids, HCC cell lines, and patient specimens.
Main Results:
- Combination therapy significantly prolonged mouse survival versus monotherapy.
- E7386 induced activating transcription factor 4 (ATF4) activation and the integrated stress response.
- E7386 potentiated lenvatinib's antiangiogenic effects, increasing antitumor efficacy.
- ATF4 upregulation and tumor shrinkage (>30%) observed in patients treated with E7386 + lenvatinib.
Conclusions:
- E7386 sensitizes HCC tumors to lenvatinib, enhancing survival through ATF4 signaling.
- The combination therapy demonstrated significant antitumor activity and tumor shrinkage in patients.
- This approach offers a potential new strategy for treating CTNNB1-mutant HCC.
