Effect of inhibiting pathogen recognition receptor function with small molecules on ovarian cancer cells in vitro 2258086

Abstract

Abstract Introduction The American Cancer Society estimates that within the year of 2025, around 20,000 women in the USA will receive a diagnosis of ovarian cancer (OvCa). Until the advent of PARP inhibitors (PARPis), the standard-of-care for first-line treatment of advanced ovarian cancer consisted of cytoreductive surgery and chemotherapy. Even with the use of PARPis, OvCa has poor survival outcomes, with only around 40% and 20% of women in average surviving 5 years after diagnosis (stage III and IV respectively). Thus, new treatments are needed to improve the outcomes for people with this disease. Pathogen recognition receptors (PRRs) are a group of immune proteins that recognize and bind structures that are highly conserved on many pathogens. In case of a viral infection, upon binding to their respective viral ligands, PRRs activate a signal cascade and ultimately cause downstream effects such as the release of cytokines, leading to an antiviral response. PRRs have been involved both in tumor resistance and progression and we speculate that targeting these molecules in tumor cells can be a future therapeutic option. Methods In these studies, we treated mouse (ID8 and BPPNM) and human (A2780, SKOV3) OvCa cells with small molecule inhibitors of TLR3 (Cu-CPT4a), TLR4 (TAK242), TLR7 &9 (E6446), PKR (PKR-IN-C16), RIG (RIG-012), and STING (H-151). We investigated the effect of the drugs on tumor cell viability, migration, and generation of spheroids and their synergism with oncolytic herpesvirus (DNA genome) and reovirus (RNA genome). Results We observed that of all the drugs studied, RIG-012 and E6446 had the highest capability to inhibit, in a dose-dependent fashion, the proliferation, migration and spheroid size of mouse and human OvCa cell cultures. In addition, E6446 was able to increase the efficacy of oncolytic herpesvirus on human ovarian cancer cells. Conclusion These findings suggest that targeting particular PRR in cancer cells could be a therapeutic approach for OvCa. Funding Source Ohio University-HCOM RSAC grant RP2404 (FB) Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)