Abstract PR08: Ubiquitin-specific protease 6 (USP6) oncogene confers sensitivity of Ewing sarcoma to interferon cytotoxicity

Abstract

Abstract Our goal is to identify novel targeted therapies for Ewing sarcoma (ES). ES is a devastating malignancy that predominantly affects children and young adults. It is the second most common cancer of the bone, yet in contrast to many other malignancies, survival rates have not improved for decades. For patients with localized disease, no biomarkers exist to predict recurrence or response to chemotherapy. For those with metastatic disease, chemotherapy is largely ineffective, and 5-year survival rates have stagnated at approximately 20%. Thus, there is an urgent need to identify biomarkers that can predict recurrence and response to therapy, as well as identify novel targeted therapies to combat this lethal disease. USP6 is the key etiologic agent in several benign bone and soft tissue tumors (BSTTs), where its chromosomal translocation results in overexpression. USP6 encodes a deubiquitylating enzyme, and our prior studies identified the tyrosine kinase Jak1 as an essential substrate of USP6 during BSTT development. Jak1 levels are dramatically elevated in USP6-overexpressing cells, leading to phosphorylation and activation of STAT transcription factors. We recently discovered that USP6 is also highly expressed in multiple sarcomas, including ES. Since Jak1-STATs play a central in mediating response to interferon (IFN), we hypothesized that USP6 might cause dysregulated IFN signaling in ES. Microarray and RNA-sequencing analysis revealed that USP6 by itself induced an IFN-response gene signature, both in immortalized, patient-derived ES cells and in primary human ES tumors. USP6+ ES cells were found to be exquisitely sensitive to exogenous IFN compared to USP6- ES cells, with both prolonged and heightened STAT1 and STAT3 activation observed. Furthermore, IFN selectively induced apoptosis of USP6+ but not USP6- ES cells. Gene expression analysis confirmed that in USP6+ ES cells, IFN synergistically induced expression of numerous IFN-stimulated genes (ISGs), including the pro-apoptotic ligand TRAIL. CRISPR-mediated depletion of TRAIL completely abrogated IFN-induced death of USP6+ ES cells. In sum, these results identify USP6 as a potential novel biomarker that may predict sensitivity of ES to targeted IFN therapy. This abstract is also being presented as Poster B11. Citation Format: Ian Henrich, Rob Young, Laura Quick, Xiaoke Wang, Andre Oliveira, Margaret Chou. Ubiquitin-specific protease 6 (USP6) oncogene confers sensitivity of Ewing sarcoma to interferon cytotoxicity [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr PR08.