Abstract 6952: PIM inhibition increases membrane expression of TNFRSF10B(DR5) and combination with recombinant human TRAIL synergizes to reduce renal cell carcinoma cell viability

Abstract Renal cell carcinoma (RCC) cases are on the rise globally. RCC tumors’ acquired resistance to current RCC therapies necessitates the identification of novel biomarkers and therapeutic strategies. Oncogenic PIM1 kinase is overexpressed in human RCC tissue and cell lines and is associated with worse clinical outcomes in RCC. PIM1 is an emerging clinically relevant biomarker and target in the treatment of RCC. The overexpression of PIM kinases has been previously reported in a glioblastoma model and knockdown or pharmacological inhibition of PIM kinases promoted the increased membrane expression of TNFRSF10B/DR5. Death Receptor 5 (DR5) is the specific receptor to TRAIL, a cancer-selective apoptosis-inducing ligand. A relationship between PIM kinases and regulation of DR5 expression for TRAIL-induced apoptosis is not yet described for RCC. Here we identify a potential link between PIM kinases' involvement in DR5 regulation and TRAIL apoptosis in RCC. RCC and nonmalignant renal epithelial cells were treated with PIM inhibitors (SGI-1776, TP-3654) or vehicle control for 24 hours and then evaluated for membrane DR5 levels via flow cytometry. Low doses (5µM) of PIM inhibitors were sufficient to induce the increased mean membrane expression of DR5 in 786-O cells by more than eleven fold (3.03% control vs 36.07% treated). To investigate synergism between PIM inhibitors and recombinant human TRAIL (rhTRAIL), RCC cell lines were treated with increasing concentrations of SGI-1776 or TP-3654 and rhTRAIL (TLY012) for 24 hours and assessed for viability via Cell Titer Glo assay. Combinations of PIM inhibitors and rhTRAIL reveal that PIM inhibition sensitized RCC cells to TRAIL induced apoptosis. These results reveal novel therapeutic strategies for the treatment of RCC, highlighting PIM kinases as targets to potentiate TRAIL induced apoptosis. Current studies are ongoing to understand the mechanism of PIM kinase involvement in DR5 regulation and sensitivity to TRAIL in RCC. Citation Format: Kimberly S. Meza, Wafik S. El-Deiry, Sheldon L. Holder. PIM inhibition increases membrane expression of TNFRSF10B(DR5) and combination with recombinant human TRAIL synergizes to reduce renal cell carcinoma cell viability [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 6952.