A Novel YAP1 Inhibitor targets CSCs-enriched Radiation Resistant Cells and Exerts Strong Antitumor Activity in Esophageal Adenocarcinoma

Mounting evidence suggests that the Hippo co-activator 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 (EAC). 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 EAC cell growth especially on YAP1 high expressing EAC cells both in vitro and in vivo. Remarkably, radiation resistant cells acquire strong CSC properties and aggressive phenotype, while CA3 can effectively suppresses these phenotypes by inhibiting proliferation, inducing apoptosis, reducing tumor sphere formation, and reducing the fraction of ALDH1+ cells. Further, CA3 combined with 5-FU, synergistically inhibits EAC cell growth especially in YAP1 high EAC cells. Taken together, these findings demonstrated that CA3 represents a new inhibitor of YAP1 and primarily targets YAP1 high and therapy resistant EC cells endowed with CSCs properties.

http://ift.tt/2jShiCZ