Abstract 7208: Targeting histone demethylase KDM6B to overcome cisplatin resistance in testicular germ cell tumors

Abstract Testicular germ cell tumors (TGCTs) represent the most common carcinoma of young men and are believed to arise from the transformation of primordial germ cells (PGCs). TGCTs are highly curable with platinum-based chemotherapeutics. However, resistance to cisplatin does occur, leading to therapeutic failure with very limited further therapy options. Previously we demonstrated polycomb and histone H3K27me3 methylation is repressed in cisplatin resistance TGCT cells. In TGCT patients the expression of H3K27 histone methylase EZH2 and H3K27 histone demethylase KDM6B is significantly associated with recurrence free survival. Induction of H3K27 methylation using demethylase inhibitor JSK-J4 or knockdown of KDM6B resulted in restored cisplatin sensitivity in cisplatin resistant TGCT cells. Furthermore, Inhibition of H3K27 demethylase by GSK-J4 or genetic knockdown of KDM6B sensitized TGCTs to cisplatin in vivo suggesting potential clinical utility of targeting H3K27me3 in refractory TGCTs. To explore underlying mechanisms H3K27me3 ChIP-seq was performed that demonstrated genome-wide loss of H3K27me3 in cisplatin resistant cells. Integrative analysis of H3K27me3 ChIP-Seq and transcriptomics is ongoing. Together findings suggests that repression of H3K27 methylation may be a viable approach to overcome treatment failure in cisplatin resistant TGCTs. Citation Format: Ratnakar Singh, Doha Shokry, Raya I. Boyd, Brayden C. Rennels, Christine Powell, Mehwish Kahn, Sarah J. Freemantle, Michael J. Spinella. Targeting histone demethylase KDM6B to overcome cisplatin resistance in testicular germ cell tumors [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 7208.