Abstract 5432: The role of nuclear factorκB-inducing kinase in ovarian cancer stem cells, chemoresistance, and relapse

Abstract

Abstract Ovarian cancer is the most lethal gynecological cancer in the United States, largely due to its high relapse rates. Research suggests these high relapse rates are due to cancer stem-like cells (CSCs), a subpopulation of tumor cells that are resistant to chemotherapy and have enhanced tumor-initiation capacity. Post-treatment, CSCs self-renew to re-establish new tumors, leading to recurrent disease that is now resistant to chemotherapy. Given that over-expression of NF-κB has been linked to CSCs, cancer progression, and chemoresistance in various tumors, including ovarian, studies uncovering the mechanisms of this pathway are needed to develop novel therapeutics for ovarian cancer treatment. The upstream activator of the alternative NF-κB pathway, Nuclear Factor κB-inducing Kinase (NIK), could be an enticing target for eliminating CSCs, however its function in these cells is not established. In our current studies, we show that HGSOC cells grown as CSC-enriching 3D spheroids have increased NIK expression and activity relative to monolayer cultured cells. Moreover, cells expressing CSC markers (CD117+/CD133+), have increased NIK gene expression, further supporting an association between NIK and CSC maintenance. Upon treatment with chemotherapies carboplatin and paclitaxel, NIK gene expression increased in the surviving population, indicating a role in chemoresistance. Knockdown of NIK using siRNA led to changes in alternative NF-kB transcriptional activity and higher sensitivity to carboplatin and paclitaxel relative to vehicle controls. Current studies are evaluating the role of NIK in tumor-initiation capacity, asymmetric division, proliferation, and changes in expression of stemness genes. Lastly, an in vivo relapse model will test the feasibility of using a NIK inhibitor following chemotherapy to prevent relapse and prolong survival. Findings from this work will further define the role of NF-kB pathway components in facilitating CSCs survival and re-establishment of tumors and identify a new potential target for eliminating CSCs in ovarian cancer. Citation Format: Cassidy C. Lucht, Mikella Robinson, Samuel F. Gilbert, Omar Lujano Olazaba, Carrie D. House. The role of nuclear factorκB-inducing kinase in ovarian cancer stem cells, chemoresistance, and relapse [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5432.