Abstract Introduction: Prostate cancer is the most commonly diagnosed cancer and the third leading cause of cancer-related death among men in Canada. Patients with castration-resistant prostate cancer (CRPC) are treated with various agents, including Enzalutamide, a second-generation hormone therapy that improves overall survival. However, in the long term, all patients eventually develop resistance. This highlights the critical need to better understand the mechanisms of Enzalutamide resistance in mCRPC and to identify new therapeutic strategies to improve patient outcomes. IκB kinase-epsilon (IKKε), a member of the IKK protein family, is involved in the inflammatory response and the inflammation phenotype of rheumatoid arthritis. IKKε has been identified as an oncogene, and deregulation of its expression has been associated with prostate cancer progression. Preliminary experiments conducted in our laboratory have shown an increased expression level of IKKε in Enzalutamide-resistant cell lines. We previously demonstrated that IKKε inhibitors, such as Amlexanox, reduce the proliferation of CRPC cells. Hypothesis: We hypothesize that inhibiting IKKε using Amlexanox restores sensitivity to Enzalutamide in Enzalutamide-resistant prostate cancer cells. Our overarching goal is to characterize the role of IKKε in the development of Enzalutamide resistance and to evaluate the therapeutic potential of the Amlexanox-Enzalutamide combination for treating mCRPC patients. Methodology and results: We obtained Enzalutamide-resistant and -sensitive CR cell lines derived from LNCaP. Cells have been treated with an increased dose of Amlexanox and Enzalutamide for 7 days to calculate the IC50 of each drug for each cell line. Based on these IC50, we performed real-time imaging assays using different dose combinations to determine the additive or synergistic effect of Amlexanox and Enzalutamide cotreatment. In addition, we confirmed IKKe and AR inhibition using Amlexanox and Enzalutamide, by Western blot assays. We also looked for the expression of apoptosis and senescence markers to determine the behavior of each studied PC cell line in response to treatments. Finally, we started Bulk RNA barcoding and sequencing (BRB-seq) assays on all LNCaP-derived cell lines treated with Enzalutamide and Amlexanox, alone or in combination. Conclusion: We aim to develop a combination therapy that can restore sensitivity to Enzalutamide, improve patients' quality of life, and more effectively control disease progression Citation Format: Llasera Mariana Mariana, Péant Benjamin, Mes-Masson Anne-Marie, Rodier Francis, Saad Fred Fred, Annab Fayrouz. Role of IKKε in resistance to second-generation hormonal therapy in prostate cancer abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (2Suppl): Abstract nr B020.
Mariana et al. (2026) studied this question.