# Overcoming Chemoresistance in Glioblastoma: Mechanisms, Therapeutic Strategies, and Functional Precision Medicine

## TL;DR

Glioblastoma is a deadly brain cancer that resists treatment due to tumor complexity and adaptive mechanisms, requiring new strategies like personalized drug testing to improve outcomes.

## Contribution

The paper reviews mechanisms of chemoresistance in GBM and explores functional precision medicine as a novel approach to guide treatment.

## Key findings

- GBM resistance is driven by DNA repair, apoptosis disruption, and tumor heterogeneity.
- Functional drug testing of patient-derived cells can guide personalized therapies.
- Current strategies targeting DNA repair and metabolism are limited by tumor heterogeneity.

## Abstract

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and remains highly lethal, with median overall survival rarely exceeding 15 months despite maximal surgical resection, radiotherapy, and temozolomide-based chemotherapy. Therapeutic resistance in GBM is driven by intrinsic tumor cell adaptations, extensive inter- and intratumoral heterogeneity, and microenvironmental constraints. Key mechanisms include enhanced DNA repair, disrupted apoptosis, pathway redundancy, altered drug metabolism, oxidative stress tolerance, and glioblastoma stem cell–mediated plasticity. In vivo, resistance is reinforced by the blood–brain barrier, hypoxia, stromal and immune interactions, and selective expansion of therapy-resistant clones. Current strategies to overcome resistance target DNA repair, oxidative stress, autophagy, and metabolic vulnerabilities; however, their efficacy is limited by tumor heterogeneity and delivery barriers. Precision oncology approaches are hampered by a paucity of validated predictive biomarkers, leaving many patients without actionable targets. Ex vivo functional drug sensitivity testing of patient-derived tumor cells offers a complementary strategy, directly assessing individual tumor responses and guiding rational combination therapies. This review highlights the molecular and cellular mechanisms underlying chemoresistance in GBM, examines emerging therapeutic strategies, and explores the potential of integrating personalized, functionally guided approaches into clinical management. Addressing GBM’s profound heterogeneity and adaptive plasticity is essential to improving outcomes in this aggressive and refractory malignancy.