Olaparib induced NAMPT and circPTTG1IP expression promoted cell survival and contributed to drug resistance in glioblastoma cells

Glioblastoma (GBM) is an aggressive brain cancer that is notoriously resistant to chemotherapy, particularly to Temozolomide (TMZ). In this study, we examined a patient-derived TMZ-resistant GBM cell line and assessed the effects of the PARP inhibitor Olaparib. We observed that while Olaparib exhibited significant tumor inhibition, its required dosage exceeded clinically acceptable levels. Transcriptomic analysis revealed a notable upregulation of nicotinamide phosphoribosyltransferase (NAMPT) in the surviving tumor cells, suggesting that increased intracellular NAD+ levels contributed to their resistance against both Olaparib and TMZ. By optimizing the dosages of Olaparib and FK866, a NAMPT inhibitor, we were able to develop a combination therapy that effectively killed TMZ-resistant GBM cells while adhering to clinically applicable pharmacodynamic and toxicological standards for each drug. This combination was also tested across other TMZ-resistant cell lines and 3D organoids, showing promising potential for clinical application. Additionally, through profiling plasma-detectable circRNA species from the combination treatment, we identified circPTTG1IP as a potential biomarker with negative predictive value. Further analysis indicated that circPTTG1IP might regulate NAMPT expression and NAD+ levels, potentially through its interaction with miRNAs targeting NAMPT. This research provides insights into a novel therapeutic strategy for overcoming TMZ resistance in GBM.