Abstract P20: PIM inhibition potentiates TRAIL apoptosis in renal cell carcinoma

Abstract

Renal cell carcinoma (RCC) cases are on the rise globally. RCC tumors’ acquired resistance to current RCC therapies necessitates the identification of novel therapeutic strategies and biomarkers. Oncogenic PIM1 kinase is overexpressed and associated with worse clinical outcomes in RCC. Knockdown or pharmacological inhibition of PIM kinases in glioblastoma was reported to promote the increased membrane expression of Death Receptor 5 (DR5). DR5 is the specific receptor to TRAIL, a cancer-selective apoptosis-inducing ligand. A relationship between PIM kinases and the regulation of DR5 for TRAIL-induced apoptosis is unknown in RCC. Here, we identify a potential link between PIM kinases' involvement in DR5 regulation and sensitivity to TRAIL apoptosis in RCC. Clinical data from a public dataset, Atlas of the plasma proteome in health and disease shows that patients diagnosed with RCCs have a significantly increased association with serum DR5 levels compared to healthy controls (HR=1.31, 95% CI [1.10-1.65], p=0.002). We also find that RCC cells secrete soluble DR5 into their conditioned media and are resistant to recombinant human TRAIL (rhTRAIL) treatment. Interestingly, treatment with low doses of PIM inhibitors (SGI-1776, TP-3654) results in the increased mean membrane expression of DR5 in RCC cells by more than tenfold as assessed via flow cytometry. We also identify synergism between PIM inhibitors and recombinant rhTRAIL or the small compound ONC201 (a TRAIL pathway inducer). PIM inhibition sensitizes RCC cells to reduced viability induced by rhTRAIL or ONC201. These results highlight PIM kinases as targets to potentiate TRAIL-induced apoptosis in RCC. Current studies are ongoing to understand the mechanism of PIM kinase involvement in DR5 regulation and sensitivity to TRAIL in RCC.