Effect of small molecule inhibitors of IRF3 and TBK1 signaling pathways on ovarian cancer cells 2257743

Abstract

Abstract Introduction Ovarian cancer (OvCa) is a highly lethal gynecologic cancer, often due to late diagnosis and therapy resistance. High-grade serous ovarian cancer (HGSOC) is the most prevalent and deadly subtype. In OvCa, the tumor microenvironment is highly immunosuppressive, which aids in the immune system evasion of cancer cells. The TBK1-IRF3 signaling pathway is relevant in the innate immune response, especially against viruses. Upon activation, TBK1 phosphorylates IRF3, which allows IRF3 to dimerize and move into the nucleus. There, it acts as a transcription factor to produce type I interferons, cytokines, and chemokines In tumors, depending on its level of activation, TBK1-IRF3 signaling pathway may either promote or repress malignant tumors. We are interested in the expression of this signaling pathway in tumor cells, and the possibility of targeting it as a therapeutic approach. Methods In these studies, we treated mouse (ID8 and BPPNM) and human (A2780, SKOV3) OvCa cells with inhibitors of IRF3 (BXT-795, C10 [phenylmethimazole]), TBK1(GSK-8612, MRT-67307); and TBK1 and IKKe (Amlexanox) at different concentrations. DMSO served as the vehicle control. We investigated the effect of the drugs on tumor cell viability, migration, generation of spheroids and their synergism with oncolytic herpesvirus (DNA genome) and reovirus (RNA genome). Results We observed that of all the drugs studied, BXT-795 and MRT-67307, had the highest capability to inhibit, in a dose-dependent fashion, the proliferation, migration (as determined by a scratch assay) and the size of spheroids (3D cultures) of mouse and human OvCa cells. In addition, BXT-795 was able to act synergistically with oncolytic herpesvirus and reovirus to kill human ovarian cancer cells. Conclusion These findings suggest that IRF3/TBK1 inhibition may influence metastatic potential and proliferative capacity of ovarian cancer cells and make them more prone to the action of oncolytic viruses. Funding Source Ohio University-HCOM RSAC grant RP2404 (FB) Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)