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Updated: Sep 7, 2025
The Clinical Application of Tumor Treating Fields Therapy in Glioblastoma
Published on: April 16, 2019
Temozolomide-induced guanine mutations create exploitable vulnerabilities of guanine-rich DNA and RNA regions in
Deanna M Tiek1,2, Beril Erdogdu3, Roham Razaghi3
1The Ken and Ruth Davee Department of Neurology, Lou and Jean Malnati Brain Tumor Institute, and Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Abstract:
Temozolomide (TMZ) is a chemotherapeutic agent that has been the first-line standard of care for the aggressive brain cancer glioblastoma (GBM) since 2005. Although initially beneficial, TMZ resistance is universal and second-line interventions are an unmet clinical need. Here, we took advantage of the known mechanism of action of TMZ to target guanines (G) and investigated G-rich G-quadruplex (G4) and splice site changes that occur upon TMZ resistance. We report that TMZ-resistant GBM has guanine mutations that disrupt the G-rich DNA G4s and splice sites that lead to deregulated alternative splicing. These alterations create vulnerabilities, which are selectively targeted by either the G4-stabilizing drug TMPyP4 or a novel splicing kinase inhibitor of cdc2-like kinase. Last, we show that the G4 and RNA binding protein EWSR1 aggregates in the cytoplasm in TMZ-resistant GBM cells and patient samples. Together, our findings provide insight into targetable vulnerabilities of TMZ-resistant GBM and present cytoplasmic EWSR1 as a putative biomarker.
Insights
Temozolomide resistance in glioblastoma involves guanine mutations disrupting G-quadruplexes and splicing. These create vulnerabilities targeted by new drugs, with cytoplasmic EWSR1 as a potential biomarker.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Temozolomide (TMZ) is a standard glioblastoma (GBM) treatment, but resistance is common.
- New therapeutic strategies are needed for recurrent GBM.
- TMZ targets guanine bases in DNA.
Purpose of the Study:
- Investigate G-quadruplex (G4) and splice site alterations in TMZ-resistant GBM.
- Identify new vulnerabilities and potential biomarkers in resistant GBM.
- Explore therapeutic strategies targeting these alterations.
Main Methods:
- Analyzed guanine mutations and G-quadruplex structures in TMZ-resistant GBM.
- Assessed changes in alternative splicing patterns.
- Tested efficacy of G4-stabilizing drug (TMPyP4) and splicing kinase inhibitors.
- Examined EWSR1 protein localization in GBM cells and patient samples.
Main Results:
- TMZ-resistant GBM exhibits guanine mutations that disrupt G-rich DNA G-quadruplexes.
- These mutations lead to deregulated alternative splicing.
- G4 structures and splicing alterations create vulnerabilities targetable by TMPyP4 and cdc2-like kinase inhibitors.
- EWSR1 protein aggregates in the cytoplasm of TMZ-resistant GBM cells and patient samples.
Conclusions:
- TMZ resistance in GBM involves G-quadruplex disruption and altered splicing.
- These molecular changes present targetable vulnerabilities for novel therapies.
- Cytoplasmic EWSR1 aggregation may serve as a predictive biomarker for TMZ-resistant GBM.
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