Abstract 197: Effects of three nucleoside reverse transcriptase inhibitor analogs on Stat3, NFκB, and JNK/c-Jun signaling in bone metastatic prostate cancer

Abstract Bone metastatic prostate cancer (BMPC) is the primary cause of fatality in patients with prostate cancer, and there is currently no effective treatment available. The role of the bone microenvironment in this process has led to an increased focus on the interactions between cancer cells and the bone microenvironment, particularly with osteoblasts. Our study delved into the mechanisms of interactions between prostate cancer cells (DU-145 and PC-3) and the hFOB 1.19 osteoblast cell line. We are investigating the broader effects of three different nucleoside reverse transcriptase inhibitor (NRTI) analogs, namely KBMD-E, KBMD-G, and KBMD-H, for their potential development as anti-cancer drugs. Our previous findings indicated that aPKC-ι and ζ play a role in the progression and metastasis of prostate cancer and that NRTI analogs were capable of inducing apoptosis and pyroptosis in DU-145 and PC-3 cells while showing less pronounced effects on the hFOB.1.19 cell line. Our findings revealed that osteoblasts play a crucial role in helping prostate cells thrive in the bone microenvironment by producing chemokines that promote metastasis. Current data suggested that all three NRTI analogs negatively affect three oncogenic pathways, Stat3, NFκB, and JNK/c-Jun pathways, thereby inducing apoptosis and diminishing metastatic stimulating signals in DU-145 and PC-3. Transcription factors Stat3, c-Jun, and NFκB seem to be critical in establishing the prostate cancer cells in bones. Also, data suggested that these three pathways work in tandem. Data shows that KBMD-E/G/H upregulated interleukin (IL)-18 while downregulating IL-8 and IL-6. KBMD-E/G/H can be used to disrupt critical steps of these metastatic cascades of prostate cancer cells, which can be targeted to develop customized, tailored therapies for bone metastatic prostate cancer, which merit further research. Citation Format: Wishrawana Sarathi Ratnayake, Luke Lajmi, Sloan Breedy, Aaron Todman, Karimeh Hagani, Kirpal Bisht, Mildred Acevedo-Duncan. Effects of three nucleoside reverse transcriptase inhibitor analogs on Stat3, NFκB, and JNK/c-Jun signaling in bone metastatic prostate 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 197.