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

However, it remains an undruggable target.

然而，它仍然是一个无法药物作用的目标。

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.

在这项研究中，我们研究了E7386（一种口服蛋白-蛋白相互作用抑制剂，针对CREB结合蛋白（CBP）/β-连环蛋白）与仑伐替尼联合使用时的抗肿瘤和抗血管生成活性，并阐明了E7386增强抗肿瘤反应的新作用机制。

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).

我们构建了一种基因工程的CTNNB1突变小鼠HCC模型，并将动物随机分为接受载体、E7386、仑伐替尼或联合治疗组（每组22-23只）。

We evaluated survival and analyzed the tumors transcriptomically and by IHC.

我们评估了生存情况，并通过转录组学和免疫组化（IHC）分析了肿瘤。

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).

此外，我们分析了五种患者来源的类器官、四种肝细胞癌（HCC）细胞系以及七对接受E7386联合仑伐替尼治疗的HCC患者在Ib/II期试验（NCT04008797）中的治疗前/治疗中配对样本。

Results

E7386 in combination with lenvatinib significantly prolonged mouse survival compared with monotherapy.

E7386与仑伐替尼联合使用显著延长了小鼠的生存期，与单药治疗相比。

Cell lines and patient-derived organoid data corroborated that sensitivity to E7386 involves processes beyond CBP/β-catenin interaction blockade.

细胞系和患者来源的类器官数据证实，对E7386的敏感性涉及除CBP/β-catenin相互作用阻断之外的过程。

Mechanistically, E7386 promoted activating transcription factor 4 (ATF4) activation, triggering the integrated stress response in preclinical models of HCC.

从机制上讲，E7386促进了活化转录因子4（ATF4）的激活，在肝细胞癌的临床前模型中触发了综合应激反应。

In vivo, E7386 concomitantly potentiated the antiangiogenic effects of lenvatinib, resulting in increased antitumor efficacy.

在体内实验中，E7386同时增强了仑伐替尼的抗血管生成效果，从而提高了抗肿瘤疗效。

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%.

在七名接受E7386加仑伐替尼治疗的肝细胞癌（HCC）患者中，确认有四名患者的ATF4基因表达特征上调，其中三名患者的肿瘤直径缩小了超过30%。

Conclusions

E7386 sensitized tumors to lenvatinib, thereby enhancing survival in mice compared with either monotherapy.

E7386使肿瘤对仑伐替尼敏感，从而增强了小鼠的生存率，与单独使用任一药物治疗相比，生存率有所提高。

In patients, E7386 combined with lenvatinib promoted tumor shrinkage and, in parallel, activated ATF4 signaling.

在患者中，E7386与仑伐替尼联合使用促进了肿瘤缩小，并且同时激活了ATF4信号通路。