PARP inhibitor counteracts Temozolomide Resistance in Glioblastoma Multiforme

Glioblastoma multiforme (GBM), a highly aggressive brain tumor, frequently develops resistance to temozolomide (TMZ), the current standard chemotherapy. Our study investigates the potential of combining TMZ with the poly (ADP-ribose) polymerase inhibitor Olaparib (OLA) to overcome TMZ resistance. Using in vitro models, including U251 cell lines and patient-derived GBM primary cultures, we demonstrate that OLA enhances TMZ efficacy by disrupting base excision repair and potentiating DNA damage-induced cytotoxicity. A CRISPR knockout screen identified DNA mismatch repair (MMR) gene deficiencies as key drivers of TMZ resistance, which OLA effectively counteracts. Co-treatment with TMZ and OLA significantly reduced tumor cell viability, even in MMR-deficient and MGMT-expressing contexts, suggesting a synergistic mechanism. Gene expression analysis revealed that the combination therapy impacts cell cycle regulation, stress responses, and extracellular matrix integrity, leading to mitotic catastrophe and apoptosis. These findings propose the TMZ-OLA combination as a promising therapeutic strategy for overcoming chemoresistance in GBM.