Temozolomide Resistance Mechanisms in Glioblastoma

Temozolomide (TMZ) remains the backbone of chemotherapy for glioblastoma, yet intrinsic and acquired resistance severely limit its efficacy. A principal mechanism involves elevated activity of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT), which directly reverses TMZ-induced O6-methylguanine lesions. Beyond MGMT, defects in the mismatch repair (MMR) machinery allow tumours to tolerate DNA adducts, while activation of alternative repair pathways and autophagy further attenuate drug-induced cytotoxicity. Glioblastoma stem-like cells (GSCs) contribute to recurrence owing to their enhanced DNA repair capacity and quiescent phenotype. Aberrant signalling through receptor tyrosine kinases—particularly EGFR and its mutant EGFRvIII—drives pro-survival transcriptional programmes that upregulate repair factors and suppress apoptosis. Epigenetic and post-translational modifications, including enhancer activation, lysine methylation of transcription factors and genomic rearrangements of MGMT, also shape the resistant state. Intratumoral heterogeneity, mediated by distinct molecular subtypes and regional microenvironments, underpins variable TMZ responses within a single lesion. Elucidation of these interwoven pathways has spurred biomarker development, predictive modelling and combinatorial strategies aimed at restoring chemosensitivity and improving patient survival.

Research from Nature Portfolio

Recent studies have uncovered how lysine methylation of the transcription factor NFAT5, triggered by EGFR-dependent EZH2 phosphorylation, stabilises NFAT5 in the nucleus and drives upregulation of MGMT, thereby diminishing TMZ efficacy. Targeting the methyltransferase responsible for NFAT5 modification enhances TMZ response in orthotopic and patient-derived xenograft models. Foundational work has also identified a distal enhancer element between MKI67 and MGMT promoters that, when activated in resistant lines, markedly increases MGMT expression; its deletion restores TMZ sensitivity and limits tumour proliferation. Additionally, genomic rearrangements of the MGMT locus have been shown to confer resistance independently of promoter methylation. CRISPR-engineered fusions recapitulate these rearrangements in vitro and in vivo, confirming their causal role and suggesting that detection of such events in circulating exosomes may serve as an early marker of recurrence.

Temozolomide Resistance Mechanisms in Glioblastoma publication trend

The graph below shows the total number of articles in temozolomide resistance mechanisms in glioblastoma across all publications each year (not limited to Nature Index journals).

Technical terms

MGMT: An enzyme that repairs O6-methylguanine lesions, directly counteracting TMZ-induced DNA damage.

Mismatch repair (MMR): A DNA repair system that recognises and corrects base mispairs; its dysfunction permits tolerance of alkylation adducts.

Glioblastoma stem-like cells (GSCs): A subpopulation with self-renewal capacity and enhanced DNA repair, implicated in tumour recurrence.

Autophagy: A catabolic process that degrades cellular components, which can be co-opted to mitigate chemotherapy-induced stress.

EGFRvIII: A constitutively active mutant form of EGFR commonly found in glioblastoma that drives pro-survival and repair pathways.

References

1. Lysine methylation promotes NFAT5 activation and determines temozolomide efficacy in glioblastoma. Nature Communications (2023).
2. Pharmacogenomic profiling reveals molecular features of chemotherapy resistance in IDH wild-type primary glioblastoma. Genome Medicine (2023).
3. A novel enhancer regulates MGMT expression and promotes temozolomide resistance in glioblastoma. Nature Communications (2018).
4. MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas. Nature Communications (2020).
5. Genome‐Wide CRISPR‐Cas9 Screening Identifies NF‐κB/E2F6 Responsible for EGFRvIII‐Associated Temozolomide Resistance in Glioblastoma. Advanced Science (2019).
6. Wnt/β-catenin signaling pathway induces autophagy-mediated temozolomide-resistance in human glioblastoma. Cell Death & Disease (2020).