Abstract 1612: Therapeutic co-targeting YAP1 and TAZ using antisense oligos (ASOs) suppress gastric cancer progression and peritoneal metastases

Abstract Gastric adenocarcinoma (GAC) is one of the most common malignancies worldwide and it is the fourth leading cause of cancer-related death. Peritoneal carcinomatosis (PC; malignant ascites or implants) in GAC patients is common and poses a challenge with short survival and lack of effective therapeutics. We and others have demonstrated that deregulation of the Hippo signaling pathway particularly with upregulation of its coactivators-YAP1 or TAZ drive cancer progression and metastases in gastroesophageal cancers suggesting YAP1 and TAZ are potential drug targets in solid tumors. However, discovery of effective drugs to target YAP1 or TAZ remains challenging due to the nuclear localization and lack of inhibitory pocket for YAP1 or TAZ. In this study, using scRNAseq and immunofluorescent staining, we observed that both YAP1, TAZ and their transcriptional factors-Tead1, Tead2, Tead3 and Tead4 are highly expressed in PC tumor cells and high expression of these proteins were associated with poorer prognosis. Further, we note that recently developed YAP or TAZ antisense oligonucleotides (ASO) can effectively and specifically suppress YAP or TAZ expression and transcription accompanied by decreased tumor cell invasion and tumor sphere formation. Further, we observed that YAP1 can interact with TAZ and both bind TEAD1,2,3 but not Tead4 transcriptional factors, while YAP1 ASO or TAZ ASO can decrease the interactions between YAP1 or TAZ with TEAD1,2,3 in GAC cells. Interestingly, inhibition of YAP1 or TAZ alone using the ASOs can complementarily increase the other at the protein and mRNA levels. Further, we revealed that YAP1 KO patient derived tumor cells (GA0518) are more sensitive to TAZ ASO than control cells and simultaneously inhibition of YAP1 and TAZ by ASOs reduces both YAP1and TAZ proteins and mRNA levels with significant decrease in cell proliferation and invasive capacity of YAP1 high tumor cells. Most importantly, co-targeting YAP and TAZ by the ASOs significantly attenuated progression and PC in the PDX model and sensitized to anti-PD1 immunotherapy in the KP-Luc syngeneic model. Taken together, our studies open a new avenue for developing novel therapeutic strategy by co-targeting both YAP1 and TAZ using the ASOs against GAC with PC. Keywords: Gastric Adenocarcinoma, YAP1, TAZ, Hippo pathway, Antisense Oligonucleotides (ASOs), Peritoneal Metastases, Targeted Therapy Citation Format: Jingjing Wu, Ailing Scott, Yan Xu, Yuan Li, Yibo Fan, Ruiping Wang, Xiaodan Yao, Katsuhiro Yoshimura, Melissa Pool Pizzi, Kohei Yamashita, Shan Shao, Christopher Vellano, Linghua Wang, Alexey Revenko, Eric Dolinski, Jaffer A. Ajani, Shumei Song. Therapeutic co-targeting YAP1 and TAZ using antisense oligos (ASOs) suppress gastric cancer progression and peritoneal metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1612.