Integrated genetic screening identifies FEN1 as a selective vulnerability and temozolomide resistance mediator in glioblastoma stem cells.

ABSTRACT: Glioblastoma (GBM) is an aggressive brain tumor characterized by therapy resistance and recurrence. Glioblastoma stem cells (GSCs) are key drivers of tumor maintenance, therapeutic resistance, and relapse, but targeting them remains clinically elusive due to their overlap with normal neural stem cells (NSCs) and a lack of actionable vulnerabilities. To identify selective vulnerabilities in GSCs, we performed genome-wide CRISPR-Cas9 loss-of-function screening across patient-derived GSC models under standard-of-care treatment conditions. We identified flap endonuclease 1 (FEN1), a key enzyme in DNA replication and base excision repair, as an essential gene for GSC survival, with enhanced dependency in the context of temozolomide (TMZ) treatment. Genetic knockdown of FEN1 impaired GSC prolife

SUBMITTER: Brakel BA 

PROVIDER: S-EPMC13635844 | biostudies-literature | 2026 Sep

REPOSITORIES: biostudies-literature