Abstract B09: Selective depletion of YAP1 with next-generation (constrained ethyl-cEt) antisense oligonucleotides results in tumor regression in mouse models of HCC with YAP1 activation

Abstract

Abstract The Hippo pathway plays important roles in tissue homeostasis. When dysregulated in adult tissues, however, it contributes to the development of a variety of cancers including hepatocellular carcinoma (HCC). YAP1 is the final regulator of the Hippo pathway and is associated with poor prognosis of HCC patients, and more recently has been suggested to be involved in tumor immune evasion. Here, we employed next-generation constrained ethyl (cEt) antisense oligonucleotides (ASOs) to selectively target YAP1 in the genetically engineered mouse (GEM) model of HCC (Salvador KO mice) as well as in a spontaneous carcinogen-induced model of HCC (diethylnitrosamine, DEN-induced HCC). In YAP1-activated Salvador KO mice with established HCC tumors, systemic treatment with YAP1 ASO at 25 mg/kg resulted in a marked reduction in YAP1 protein level in tumor (>90%) and regression of existing tumors, in contrast to the tumors in vehicle or control ASO-treated animals that significantly increased in size. In the DEN-induced HCC model, YAP1 was strongly activated in tumors as demonstrated by nuclear localization of YAP1 protein and the gene signature we previously identified (SOH). YAP1 ASOs produced either complete tumor stasis when DEN tumors were grown in immune-deficient mice, or complete regressions when tumors were grown in immune-competent animals. In accordance with this, YAP1 ASO treatment resulted in significant infiltration of T cells and myeloid lineage cells in the tumors in immune-competent mice. Importantly, when tumor-bearing animals were taken off the treatment after tumor regression was observed with YAP1 ASO, the antitumor response was sustained for more than 1 year, with 4 out of 16 animals remaining tumor-free in YAP1 ASO group. Furthermore, YAP1 ASO in combination with anti-PD1 antibody led to enhanced antitumor activity in the same tumor model. Collectively, these results suggest a potential therapeutic use of YAP1 ASO in the treatment of HCC with YAP1 activation as a single agent or in combination with immuno-oncology drugs. Broad screens have identified the human YAP1 ASO clinical development compound YAP1RX. Citation Format: Youngsoo Kim, Joanna Schmidt, Minji Jo, Jing Yi, Xiaolin Luo, Rachel Fleming, Sun Young Yim, Ju-Seog Lee, Brett P. Mornia, Randy L. Johnson, Gordon Mills, A. Robert MacLeod. Selective depletion of YAP1 with next-generation (constrained ethyl-cEt) antisense oligonucleotides results in tumor regression in mouse models of HCC with YAP1 activation [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr B09.