Enhanced tumor suppression in patient-derived temozolomide-resistant glioblastoma cells using a combination treatment of Olaparib and FK866.

Glioblastoma (GBM) is a prevalent brain cancer with notorious aggressiveness in adults. Standard treatment for GBM includes surgery, radiation, and administration of Temozolomide (TMZ). However, the TMZ resistance during chemotherapy poses a significant challenge. In the recent study a patient-derived TMZ-resistant GBM cell line, we found that Olaparib, a PARP inhibitor, exerted a significant tumor inhibition effect. However, the required dosage appeared to be beyond current clinical applicable levels. From a transcriptome analysis screen, a drastic upregulation of nicotinamide phosphoribosyltransferase (NAMPT) was validated in tumor cells survived from Olaparib treatments. The increased level of intracellular NAD + was sufficient to increase the cell survival from Olaparib and TMZ exposure. By optimizing the dosage of Olaparib and FK866, a NAMPT inhibitor, we were able to achieve a combination regimen allowing both effective killing and growth inhibition of TMZ-resistant GBM cells, as well as the acceptance of current clinical pharmacodynamic and toxicological standard of each component agent. The combination treatment strategy was also tested in other TMZ-resistant cell lines and 3D organoids for its potential in clinical applications. In searching for potential marker molecules to indicate the effectiveness from the double inhibition of both NAMPT and PARP activities, we profiled the plasma-detectable circRNA species of cell subjected to the combination treatments, and identified the circPTTG1IP with a negatively of predictive value. Additional investigation suggested that NAMPT expression and cellular NAD + levels were regulated by circPTTG1IP, possibly involved its interaction with NAMPT targeting miRNAs.