Abstract A04: Genetic and pharmacologic inhibition of HES1 reduces YAP1 expression, impairing rhabdomyosarcoma cell growth

Abstract

Abstract Rhabdomyosarcoma (RMS) is a mesenchymal cancer with skeletal muscle histogenesis and the most common soft-tissue sarcoma of childhood. High-risk patient groups continue to have a poor survival (<30%) and novel therapeutic targets are needed. In our studies of Hippo signaling in RMS, we found that expression of YAP1 in a human myoblast-based model of RMS is permissive for bypass of senescence, tolerance of oncogenic RAS expression, and full transformation to cells able to grow as xenografts mimicking the embryonal variant of RMS (ERMS). In parallel, we found that YAP1 engages in a positive feedback loop with the Notch signaling pathway, suggesting that Notch effectors must impact downstream YAP1. Here we show that shRNA-mediated suppression of the basic helix-loop-helix transcriptional repressor and Notch effector, HES1, inhibits ERMS cell growth in vitro. Mechanistically, HES1 suppression causes decreased levels of YAP1 mRNA and protein, and increased mRNA and protein levels of the cell cycle regulator and tumor suppressor CDKN1C (P57kip2) across three different cell lines. Additionally, HES1 suppression results in cell line-specific increases in the myogenic markers MYOD1, MYOG, and MYF6. Recently, Perron et al. reported that the small molecule JI051 inhibits HES1 by stabilizing its interaction (doi:10.1074/jbc.RA118.002316) with the protein chaperone prohibitin-2, thus sequestering HES1 outside the nucleus. We demonstrate that JI051 inhibits ERMS cell growth in vitro with EC50 values in the low nanomolar range. Preclinical in vivo studies combining HES1 inhibition and YAP1 inhibition are planned, with the hypothesis that their coinhibition could prove effective in mitigating treatment resistance. A full understanding of the relationship between HES1 and YAP1 signaling will be paramount in moving compounds such as JI051 from the laboratory to the clinic. Citation Format: Alexander R. Kovach, Corinne M. Linardic. Genetic and pharmacologic inhibition of HES1 reduces YAP1 expression, impairing rhabdomyosarcoma cell growth [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 A04.