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Updated: Jan 13, 2026
The Clinical Application of Tumor Treating Fields Therapy in Glioblastoma
Published on: April 16, 2019
The Temozolomide Mutational Signature: Mechanisms, Clinical Implications, and Therapeutic Opportunities in Primary
Adar Yaacov1,2, Roni Gillis1,2, Jaber Salim1,2
1Helmsley Cancer Center, Shaare Zedek Medical Center, Jerusalem 9103102, Israel.
Abstract:
Temozolomide (TMZ) remains foundational in the management of adult-type diffuse gliomas in general, and glioblastoma specifically. However, its efficacy harbors an evolutionary trade-off. TMZ drives its cytotoxicity through generating O6-methylguanine lesions, especially active in MGMT-silenced, mismatch repair (MMR)-proficient tumors. By selecting for acquired MMR-deficient subclones, often via MSH6 inactivation, this process escalates into a hypermutator phenotype, generating thousands of de novo alterations. This is a hallmark of the mutational signature known as SBS11, characterized by C>T transitions, which is associated with TMZ treatment. The hypermutator phenotype drives heterogeneity, therapeutic resistance, spatial diversification, and distant recurrence. Despite harboring a mutational burden comparable to melanoma and lung cancer, TMZ-induced hypermutation does not sensitize gliomas to immune checkpoint blockade. This resistance reflects the profoundly immunosuppressive brain microenvironment, impaired antigen presentation, marked transcriptional plasticity, and perhaps also the frequent use of corticosteroids. Emerging strategies aim to exploit vulnerabilities created by TMZ-mediated genomic instability, including PARP, ATR, WEE1, and AURKA inhibition; alternative alkylators; metabolic rewiring; and G-quadruplex stabilization. Notably, the real-time detection of evolving mutational signatures via CSF-based liquid biopsies may enable adaptive therapy before radiographic progression. By reframing TMZ as a potent evolutionary agent rather than a conventional chemotherapy, this review synthesizes recent mechanistic insights and translational opportunities to guide a next-generation, evolution-informed treatment paradigm for glioma.
Insights
Temozolomide (TMZ) treatment for gliomas drives tumor evolution by creating a hypermutator phenotype. This acquired resistance limits immunotherapy effectiveness, necessitating new evolution-informed treatment strategies.
Area of Science:
- Neuro-oncology
- Cancer Genomics
- Evolutionary Medicine
Background:
- Temozolomide (TMZ) is a standard glioma treatment, particularly for glioblastoma.
- Its efficacy is limited by acquired resistance mechanisms.
- TMZ induces DNA damage, selecting for specific tumor subclones.
Purpose of the Study:
- To review the evolutionary consequences of TMZ treatment in gliomas.
- To explore mechanisms of TMZ resistance and therapeutic challenges.
- To discuss emerging strategies for overcoming TMZ-induced resistance.
Main Methods:
- Literature review synthesizing mechanistic insights and translational opportunities.
- Analysis of molecular mechanisms of TMZ cytotoxicity and resistance.
- Discussion of novel therapeutic targets and adaptive treatment approaches.
Main Results:
- TMZ selects for mismatch repair-deficient (MMR-d) subclones, leading to a hypermutator phenotype (SBS11 signature).
- This hypermutation drives tumor heterogeneity, resistance, and recurrence, but not sensitivity to immune checkpoint blockade.
- Resistance is linked to the brain's immunosuppressive microenvironment and other factors.
Conclusions:
- TMZ acts as an evolutionary agent, shaping glioma progression.
- Exploiting TMZ-induced genomic instability offers therapeutic opportunities (e.g., PARP, ATR inhibitors).
- Evolution-informed, adaptive therapies, potentially guided by liquid biopsies, are crucial for future glioma treatment.
