Abstract 185: Alternative NF-kB inhibits MAPK activity to promote quiescence and drug resistance in ovarian cancer

Abstract Ovarian Cancer (OC) is the most lethal gynecological malignancy in the United States and despite good initial response to chemotherapy, approximately 80% of late-stage patients relapse. Recent studies suggest that a subpopulation of tumor cells with stem-like characteristics, called Cancer Stem-like Cells (CSCs), resist treatment and drive recurrence. Several signaling pathways, including MAPK and NF-kB, are known for their roles in tumor initiation, disease progression, and drug resistance in ovarian cancer. We previously showed that the canonical NF-kB factor, RelA, primarily promotes proliferation, while the non-canonical NF-kB factor, RelB, promotes quiescence. Additionally, activation of MAPK/ERK has been implicated in proliferation of ovarian cancer cells. NF-kB and MAPK signaling cascades are both critical for OC progression, although their precise roles in maintaining CSCs remain unclear. Our preliminary data showed that knockdown (KD) of RelB in vivo following chemotherapy did not decrease growth of residual tumors, whereas KD of RelA or inhibition of MAPK alone reduced growth of residual tumors. However, combining RelB KD with MAPK inhibition reduced growth of residual tumors comparable to RelA KD or MAPK inhibition alone. Therefore, we hypothesize that RelB supports quiescence in CSCs by downregulating MAPK activity. Western Blot analysis indicated increased MAPK activity in the absence of RelB in two high grade serous ovarian cancer (HGSOC) cell lines. Moreover, in vitro cell cycle studies revealed an increase in the percentage of CSCs in the S phase following RelB KD and combining RelB KD with MAPK inhibition rescued this phenotype. Taken together, our findings suggest that RelB downregulates MAPK activity to support quiescence in ovarian CSCs. Ongoing studies are investigating the expression of S phase specific cyclins in the absence of RelB to further elucidate mechanisms of proliferation and cell cycle progression regulated by RelB and MAPK. Additionally, immunohistochemistry (IHC) analysis using tissues derived from control, RelB KD, and RelB KD with MAPK inhibition tumors will be used to evaluate changes in NF-kB, MAPK and cell cycle proteins in residual and regrown tumors. This work reveals novel mechanisms of how RelB supports drug resistance in ovarian CSCs and information gleaned from this study could inform future therapeutic studies. Citation Format: Cecilia Gallo, Mikella Robinson, Jacqueline Lara, Omar Lujano Olazaba, Carrie D. House. Alternative NF-kB inhibits MAPK activity to promote quiescence and drug resistance in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 185.