Inhibition of malignant progression in mesenchymal glioblastoma by PARP1 inhibitors
Year: 2026
Type: article
Abstract: Background: Among molecular subtypes of glioblastoma (GBM), the mesenchymal subtype (MES) exhibits the most aggressive clinical course, marked by heightened invasiveness and therapeutic resistance.Methods: To overcome the challenge of intrinsic drug resistance in MES GBM, we performed a high-throughput screen of 2,697 Food and Drug Administration (FDA)-approved compounds on NF1-silenced human GBM cells, engineered via CRISPR/Cas9.Results: This screen nominated poly(ADP-ribose) polymerase 1 (PARP1) inhibitors as top candidates, demonstrating selective cytotoxicity against NF1-deficient cells. Integrated analyses of The Cancer Genome Atlas (TCGA) data, immunofluorescence, and immunoblotting revealed significant PARP1 upregulation in GBM tissues, establishing its role as a proto-oncogene that drives tumor cell proliferation and migration. Using orthotopic xenograft models, we confirmed that NF1 knockdown (KD) profoundly sensitized GBM tumors to the anti-tumor and pro-apoptotic effects of PARP1 inhibition in vivo. Mechanistically, co-immunoprecipitation (co-IP) assays identified a physical interaction between the NF1 gene product neurofibromin and PARP1, suggesting a direct regulatory nexus.Conclusions: This study breaks through the traditional limitation of PARP inhibitors being used only for DNA repair defects, and for the first time reveals a novel selective killing mechanism of PARP1 inhibitors in NF1-deficient GBM. Collectively, our findings delineate NF1-mutant, MES GBM as a distinct clinical subset poised to derive therapeutic benefit from PARP1-targeted therapy.
Source: Translational Cancer Research
Institution: Lanzhou University Second Hospital
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7224118817