Nuvisertib (TP-3654) and Dordaviprone (ONC201) synergize to reduce renal cell carcinoma cell viability

The Incidence of renal cell carcinoma (RCC) continues to increase in the United States, ranking among the ten most frequently diagnosed cancers in men and women. Unfortunately, resistance to existing treatments remain a major obstacle, driving the need for identification of clinically relevant biomarkers and therapeutic targets. TNF-related apoptosis inducing ligand (TRAIL) is a promising cancer therapy that selectively induces apoptosis in malignant cells while sparing normal cells. TRAIL exerts its cytotoxic effects through binding death receptors DR4 and DR5, initiating caspase dependent programmed cell death. However, intrinsic and acquired resistance mechanisms have limited TRAIL's efficacy as anti-cancer strategy. We have identified a link between the overexpression of oncogenic PIM kinases and regulation of DR5 expression and sensitivity to TRAIL apoptosis in RCC. PIM1 is emerging as a clinically relevant biomarker and therapeutic target in RCC. Nuvisertib (TP-3654) is a selective PIM1 kinase inhibitor currently being evaluated in Phase 1/2 clinical trials for patients with myelofibrosis and has received FDA fast track designation. We find that treatment of RCC cells with low dose (2.5 µM) of Nuvisertinib over 24 hours induces a 5.75-fold (p<0.01) increased mean membrane expression of DR5 compared to vehicle control assessed by flow cytometry. We also investigated synergism between Nuvisertib and Dordaviprone, a newly FDA approved imipridone and TRAIL inducer. We evaluated combinations of Nuvisertib and Dordaviprone via Cell Titer Glo in RCC cells and find that combination indices indicate synergism which significantly reduce RCC cell viability more potently than either agent alone. Our findings highlight actionable novel candidate targets and strategies for therapeutic intervention in RCC. Ongoing studies are aimed to uncover mechanistic insights of these treatments in RCC and guide the development of optimal treatment strategies.