Abstract 2094: Prostaglandin E receptor 3 mediates resistance to tumor treating fields in glioblastoma cells

Abstract

Abstract Glioblastoma (GBM) is the most common and deadliest malignant brain cancer in adults despite surgery and aggressive chemoradiotherapy. Tumor Treating Fields (TTFields) have been approved in combination with adjuvant temozolomide chemotherapy for newly diagnosed 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, leading to disrupted chromosomal segregation and cell death. However, treatment resistance develops in many TTFields responders. The mechanism of TTFields resistance remains largely unexplored. Understanding how GBM cells circumvent the biophysical forces of TTFields and their downstream effects will provide new opportunities to improve therapeutic efficacy of this novel anti-cancer treatment. To accomplish these objectives, we have developed several human GBM cell lines that demonstrated relative resistance to the cytotoxic effects of TTFields compared to the parental cells. Importantly TTFields-induced chromosomal instability such as the formation of cytoplasmic micronuclei was preserved in resistant cells compared to their sensitive counterparts, indicating resistance to TTFields is mediated through a non-bioiphysical mechanism. Indeed, TTFields-induced inflammatory response was severely suppressed in resistant cells, supporting the hypothesis that that resistance to TTFields is conferred by a selective loss of the deleterious effects induced by the biophysical insults. Importantly, this acquired TTFields resistance phenotype was associated with a transition to a stem-like state as determined by a standard neurosphere assay. Using a systems approach aided by a suite of innovative computational platforms, we methodically dissected this stemness program in resistant cells to identify master regulators of the resistance mechanism. Interestingly, 3 networks were found disrupted, including nervous system developmental regulation, inflammatory response and cell-cell adhesion, all of which play critical roles in GBM stem-like cells, thus confirming our initial hypothesis. Utilizing a unique master regulator ranking system, we successfully identified Prostaglandin E Receptor 3 (PTGER3) as a key master regulator at the apex of these pathways and responsible for the resistant phenotype. PTGER3 is rapidly upregulated in GBM cells when exposed to TTFields and appears to channel treated cells away from the beneficial inflammatory pathways that TTFields also activates in parallel. Ongoing experiments are aimed at understanding the molecular mechanism of PTGER3-dependent TTFields resistance. Our goal is to develop targeted therapies to overcome resistance to TTFields. Note: This abstract was not presented at the meeting. Citation Format: Dongjiang Chen, Son Le, Nagheme Thomas, Changwang Deng, Dan Jin, Mathew Sebstian, Jie Ren, David Tran. Prostaglandin E receptor 3 mediates resistance to tumor treating fields in glioblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2094.