Mounting evidence suggests that the Hippo coactivator Yes-associated protein 1 (YAP1) is a major mediator of cancer stem cell (CSC) properties, tumor progression, and therapy resistance as well as often a terminal node of many oncogenic pathways. Thus, targeting YAP1 may be a novel therapeutic strategy for many types of tumors with high YAP1 expression, including esophageal adenocarcinoma. However, effective YAP1 inhibitors are currently lacking. Here, we identify a small molecule (CA3) that not only has remarkable inhibitory activity on YAP1/Tead transcriptional activity but also demonstrates strong inhibitory effects on esophageal adenocarcinoma cell growth especially on YAP1 high–expressing esophageal adenocarcinoma cells both in vitro and in vivo. Remarkably, radiation-resistant cells acquire strong cancer stem cell (CSC) properties and aggressive phenotype, while CA3 can effectively suppress these phenotypes by inhibiting proliferation, inducing apoptosis, reducing tumor sphere formation, and reducing the fraction of ALDH1+ cells. Furthermore, CA3, combined with 5-FU, synergistically inhibits esophageal adenocarcinoma cell growth especially in YAP1 high esophageal adenocarcinoma cells. Taken together, these findings demonstrated that CA3 represents a new inhibitor of YAP1 and primarily targets YAP1 high and therapy-resistant esophageal adenocarcinoma cells endowed with CSC properties. Mol Cancer Ther; 17(2); 443–54. ©2017 AACR.

中文翻译：

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一种新型 YAP1 抑制剂靶向富含 CSC 的抗辐射细胞并在食管腺癌中发挥强大的抗肿瘤活性

越来越多的证据表明，Hippo 辅激活因子 Yes 相关蛋白 1 (YAP1) 是癌症干细胞 (CSC) 特性、肿瘤进展和治疗抗性的主要介质，并且通常是许多致癌途径的终末节点。因此，针对 YAP1 高表达的多种类型的肿瘤，包括食管腺癌，靶向 YAP1 可能是一种新的治疗策略。然而，目前缺乏有效的 YAP1 抑制剂。在这里，我们鉴定了一种小分子（CA3），它不仅对 YAP1/Tead 转录活性具有显着的抑制活性，而且在体外和体内对食管腺癌细胞的生长，尤其是对 YAP1 高表达的食管腺癌细胞的生长显示出强烈的抑制作用。值得注意的是，抗辐射细胞获得强大的癌症干细胞 (CSC) 特性和侵袭性表型，而 CA3 可以通过抑制增殖、诱导细胞凋亡、减少肿瘤球形成和减少 ALDH1+ 细胞的比例来有效抑制这些表型。此外，CA3 与 5-FU 结合可协同抑制食管腺癌细胞的生长，尤其是在 YAP1 高食管腺癌细胞中。综上所述，这些发现表明 CA3 代表了一种新的 YAP1 抑制剂，主要靶向具有 CSC 特性的 YAP1 高和耐药性食管腺癌细胞。摩尔癌症治疗; 17(2); 443-54。©2017 AACR。并减少 ALDH1+ 细胞的比例。此外，CA3 与 5-FU 结合可协同抑制食管腺癌细胞的生长，尤其是在 YAP1 高食管腺癌细胞中。综上所述，这些发现表明 CA3 是一种新的 YAP1 抑制剂，主要靶向具有 CSC 特性的 YAP1 高和抗治疗食管腺癌细胞。摩尔癌症治疗; 17(2); 443-54。©2017 AACR。并减少 ALDH1+ 细胞的比例。此外，CA3 与 5-FU 结合可协同抑制食管腺癌细胞的生长，尤其是在 YAP1 高食管腺癌细胞中。综上所述，这些发现表明 CA3 是一种新的 YAP1 抑制剂，主要靶向具有 CSC 特性的 YAP1 高和抗治疗食管腺癌细胞。摩尔癌症治疗; 17(2); 443-54。©2017 AACR。