Abstract AP32: THE ROLE OF NFAT3 IN OVARIAN CANCER QUIESCENCE AND CHEMOTHERAPY RESISTANCE
Authors: Cole Alex J , Iyengar Mangala , O'Hayer Patrick , Yang Kun , Sebastian Tara , Coffman Lan , Buckanovich Ronald J 
Published: June 2021

Despite the fact that the majority of patients with ovarian cancer will have a complete clinical remission with combined surgical/chemotherapeutic approaches, Epithelial Ovarian Cancer (EOC) is the fifth most common cause of cancer-related death in American women, with the third highest mortality:incidence ratio. The majority of deaths from ovarian cancer are related to disease recurrence and the subsequent development of ultimately fatal chemotherapy-resistant disease. Elucidating mechanisms of chemoresistance in ovarian cancer cells may identify critical therapeutic targets to prevent or treat relapsed ovarian cancer. One feature that might contribute to the chemotherapy resistance is quiescence.

Quiescence describes a reversible non-proliferative cell state. As such, quiescent cells have reduced susceptibility to chemotherapeutics which target rapidly proliferating cells. Indeed, quiescence is a known mechanism of chemotherapy resistance of normal stem cells. In normal stem cells quiescence is mediated by the NFAT family of transcription factors. Unfortunately, very little is known about the factors that mediate ovarian cancer cell quiescence. Using qRT-PCR, we evaluated the expression of NFAT family members in ovarian cancer cells. We found NFAT3 to be enriched in patient ovarian cancer stem-like cells (CSLC) compared to bulk cancer cells. Treatment of EOC cells with cisplatin chemotherapy resulted in a nuclear translocation of NFAT3 and increase in NFAT3 transcriptional activity. To directly investigate the functional role of NFAT3 in ovarian cancer, we created ovarian cancer cell lines expressing constitutively nuclear/active (cNFAT3) or inducible constitutively active (IcNFAT3) NFAT3. We found that while cNFAT3 expression in ovarian cancer cells did not impact cell viability, senescence or apoptosis, cNFAT3 expression profoundly restricted ovarian cancer cell proliferation, with a 3-fold decreased cell division rates, and cellular arrest in the G0 phase of the cell cycle. Consistent with a quiescent cell phenotype, this was associated with a 10% decrease in cell size, and a 25% decrease in total cellular RNA. Induction of cNFAT3 expression in vivo resulted in tumor growth arrest. This growth arrest resulted in chemotherapy resistance such that cNFAT3 tumors treated with high dose of chemotherapy rapidly expanded after cNFAT3 inactivation. Furthermore, NFAT inhibition with the peptide inhibitor VIVIT enhance chemotherapy response in vitro and in vivo.

Taken together, our data suggests NFAT3 drives a quiescent state in CSLC and thereby mediates chemoresistance. Thus NFAT3 represents a therapeutic target to both overcome chemotherapy resistance in quiescent cancer cells and to restrict the growth of therapy-resistant disease.

Citation Format: Alex J Cole, Mangala Iyengar, Patrick O'Hayer, Kun Yang, Tara Sebastian, Lan Coffman, Ronald J Buckanovich. THE ROLE OF NFAT3 IN OVARIAN CANCER QUIESCENCE AND CHEMOTHERAPY RESISTANCE [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr AP32.