Introduction:

Renal cell carcinoma (RCC) is the sixth most common cancer in the US. Tyrosine kinase inhibitors and mTOR inhibitors are effective initially, but resistance develops. Hence, the need to develop combinatorial options to overcome resistance is paramount. We showed recently that poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) can be viable therapeutics against RCC. The objective of this study was to determine whether PARP inhibition synergizes with sunitinib or everolimus against RCC cells.

Methods:

To determine the efficacy of PARPi combination with sunitinib or everolimus, we treated a human normal renal cell line RPTEC/TERT1 and two human renal cancer cell lines ACHN and CAKI-2 with PARPi niraparib, olaparib, rucaparib, or talazoparib with sunitinib or everolimus. Cell survival, cell proliferation, and cell viability were assessed. 3-D spheroids of RCC cells were generated and treated with the combination of sunitinib or everolimus with PARPi. Spheroid viability was quantified using fluorescence. Metabolic profiles of treated cells were assessed with the Seahorse system.

Results:

Treatment with PARPi potentiated cell killing by both sunitinib and everolimus in vitro. 3-D spheroids responded better to a combination of everolimus with PARPi. The combinations of niraparib and talazoparib with sunitinib or everolimus were the most effective in reducing cell viability of RCC cells. Treatment with a combination of PARPi and sunitinib or everolimus reduced glycolytic activity in RCC cells.

Conclusion:

PARP inhibition may potentiate and synergize with known therapies to treat RCC. Combination therapies with PARPi may be useful in certain circumstances or as a second-line therapy.   

Funding: This work was supported in part by NCI grants R21CA203406, R03CA198696, and the College of Medicine and Life Sciences, University of Toledo (NN) and an Endowed Chair from the Stranahan Foundation for Oncological Research Toledo, Ohio (FP).