Ex vivo therapy-driven selection of glioblastoma stem-like cells models resistance evolution

Glioblastoma (GBM) remains lethal, creating an urgent need for experimental models of therapy- specific resistance evolution. Within-patient GSC models were developed by parallel ex-vivo selection under temozolomide (TMZ-GSC) or ionizing radiation (IR-GSC), alongside untreated controls (CTRL- GSC). • O6-methylguanine-DNA methyltransferase (MGMT) expression was confirmed as a determinant of primary TMZ resistance and was maintained during GSC evolution. • In MGMT-negative GSCs, primary TMZ sensitivity evolved into stable secondary resistance through mismatch-repair gene inactivation, recapitulating patient findings, or was retained along with a newly identified drug-tolerant phenotype. • Primary radioresistance was commonly observed, while its further evolution was associated with more efficient DNA double-strand-break repair and enrichment of homologous- recombination and checkpoint-control transcriptional programs. • In GSCs emerging after either TMZ or IR, broad transcriptional patient-specific programs and classification-relevant subtypes were largely preserved. • Across treatments, GSC evolution was accompanied by shared genome-maintenance and mitotic chromosome-segregation transcriptional programs and increased RTK expression and activity, collectively promoting recovery after genotoxic stress.

• Type: Cancer Genomics
• Archive: European Genome-phenome Archive (EGA)