DRES-06. PROSTAGLANDIN E RECEPTOR 3 MEDIATES RESISTANCE TO TUMOR TREATING FIELDS IN GLIOBLASTOMA CELLS
Abstract OBJECTIVES Tumor Treating Fields (TTFields) are approved in combination with temozolomide for newly diagnosed glioblastoma (GBM). The addition of TTFields resulted in a significant improvement in overall survival. TTFields are low-intensity alternating electric fields that are thought to disturb mitotic macromolecules’ assembly. However, most GBM patients eventually develop resistance to TTFields. The mechanism of TTFields resistance remains largely unexplored. Understanding how GBM cells circumvent the biophysical forces of TTFields and their downstream effects will improve therapeutic efficacy of this novel anti-cancer treatment modality. METHODS A panel of GBM cell lines were treated continuously with TTFields at the clinically approved frequency of 200 kHz using an in vitro TTFields system until cells with relative resistance to the cytotoxic effects of TTFields. A systems approach aided by innovative network ranking computational algorithms were utilized to analyze global gene expression profiles and identify resistance pathways, which were subsequently validated experimentally. RESULTS TTFields-induced chromosomal instability such as the formation of cytoplasmic micronuclei is preserved in resistant cells, indicating that TTFields resistance is mediated through a non-biophysical mechanism. This acquired TTFields resistance phenotype is associated with a transition of GBM cells to a stem-like state as determined by a neurosphere assay. Using an innovative computational platform, we methodically dissected this stemness program in resistant cells. Mechanistically, Prostaglandin E Receptor 3 (PTGER3) is the top ranked master regulator responsible for resistance. PTGER3 is rapidly upregulated in GBM cells upon exposure to TTFields and further increases with prolonged treatment as resistance sets in. Pharmacological inhibition of PTGER3 either using aspirin to reduce prostaglandin E production or PTGER3-specific inhibitors resensitized cells to TTFields. CONCLUSIONS We have identified a novel pathway with PTGER3 at the apex that plays a critical role in TTFields resistance. This pathway is a potential therapeutic target to reduce resistance to TTFields therapy in GBM.