Abstract 2621: TNFRSF19 (TROY) promotes glioma cell survival signaling and therapeutic resistance.

Glioblastoma multiforme (GBM) is the most common primary central nervous system tumor accounting for approximately 40% of all primary malignant brain tumors. The mechanism driving the development and recurrence of GBM is still largely unknown which greatly limits the successful treatment of this disease. The tumor necrosis factor receptor superfamily member TNFRSF19 (TROY) is a type I cell surface receptor protein containing the highly conserved TNFR cysteine-rich motifs in the extracellular domain and a tumor necrosis factor-receptor-associated factor (TRAF) - binding sequence in the cytoplasmic domain. We recently demonstrated that increased expression of TROY stimulated glioma cell migration in vitro and increased cell invasion in an organotypic brain slice model. Conversely, siRNA mediated knockdown of TROY expression inhibited glioma cell migration. In addition, profiling of TROY in brain tumor samples indicated that TROY mRNA expression was significantly increased in GBM samples, directly correlated with increasing glial tumor grade, and inversely correlated with patient outcome suggesting that TROY expression may play a role in GBM invasion and is a good indicator of survival outcome. In the current study, we investigated the role of TROY in therapeutic resistance and survival signaling. We report that TROY protein expression was significantly increased in patient GBM tumor samples with TROY mRNA exhibiting increased expression in the invasive cell population. Aberrant expression of TROY in mouse astrocytes in situ using glial-specific gene transfer in transgenic mice induced astrocyte migration within the brain supporting an important role for TROY in glioma cell migration. Notably, increased TROY expression did not increase cell proliferation but increased resistance of glioma cells to both radiation and temozolomide induced apoptosis while knockdown of TROY increased temozolomide sensitivity. TROY induced resistance to TMZ was dependent upon Akt and NF-κB activation. We also report that TROY induced NF-κB phosphorylation and stimulation of migration required the membrane proximal region of the TROY cytoplasmic domain and that knockdown of TROY expression increased survival in a xenograft model. The current results further support a role for TROY in GBM and suggest that targeting TROY and its signaling pathway represents a potential approach to increase tumor vulnerability and improve the therapeutic response of glioblastoma. Citation Format: Harshil D. Dhruv, Serdar Tuncali, Jean Kloss, Zhongbo Yang, Cassie Schumacher, Bart Williams, Julianna Ross, Nhan Tran, Joseph Loftus. TNFRSF19 (TROY) promotes glioma cell survival signaling and therapeutic resistance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2621. doi:10.1158/1538-7445.AM2013-2621