Janah Dia

Background: Glioblastoma multiforme (GBM), a WHO grade IV glioma, is the most common and aggressive primary brain tumor in adults. It is characterized by poor prognosis and high resistance rate to aggressive multimodal therapy. Standard therapy protocol involves maximal surgical resection followed by radiation and temozolomide (TMZ) chemotherapy. The aggressive nature of GBM is partially due to the expression of DNA repair enzymes such as MGMT and APNG and survival of glioma stem cells (GCSs). Emerging research has identified METTL3 catalyzed m6A RNA modifications as a critical epigenetic mechanism which contributes to the resistance mechanism of glioma cells to TMZ and radiation. METTL3 also stabilizes transcripts involved in DNA repair and cell survival making it a promising molecular target in the treatment of GBM.^1-3

Objective: This review examines how METTL3-mediated m6A RNA methylation contributes to therapy resistance in GBM and asseses the potential of METTL3 inhibition as a novel therapeutic strategy.

Search Methods: A literature review was conducted using PubMed and ClinicalTrials.gov databases. The search was limited to peer-reviewed studies published between 2017 and 2025. Articles were identified using MeSH terms and keywords included “glioblastoma”, “METTL3”, “m6A methylation”, “temozolomide resistance”, and “glioma stem cells.” Primary articles were selected based on experimental rigor, relevance to METTL3 mechanisms, and translational potential.

Results: Several studies demonstrated that METTL3 promotes resistance to TMZ by methylating and stabilizing mRNAs encoding MGMT and APNG which enhances DNA repair capabilities.¹ m6A modification increases transcript stability and allows these DNA repair enzymes to escape degradation and repair TMZ-induced damage.¹ METTL3 knockdown in both glioma cells and GSCs increased DNA damage, apoptosis, and transcript degradation thereby increasing sensitivity to TMZ.² These mechanisms were confirmed using actinomycin D chase assays and γ-H2AX staining. These effects are also observed in glioma stem cells which indicates that METTL3 sustains therapy-resistant cell populations. Additionally, TMZ upregulates METTL3 expression via SOX4 mediated histone acetylation and H3K27 acetylation which creates a positive feedback loop that further amplifies therapy resistance.³ METTL3 also stabilizes the long noncoding RNA LINC00839 which activates the Wnt/β-catenin pathway promoting radiation resistance in GSCs.⁴ These mechanisms collectively show METTL3 plays a multifaceted role in sustaining GBM cell survival and promoting therapy resistance.

Conclusion: Collectively, these findings show that METTL3-mediated m6A methylation plays a crucial role in glioblastoma therapy resistance to both chemotherapy and radiation by stabilization of survival and DNA repair transcripts. This mechanism is seen in both bulk tumor cells and glioma stem cells and positively regulated by TMZ itself.  The development and early clinical testing of METTL3 inhibitors such as STC-15 represent a significant step towards improving the prognosis and patient outcomes in GBM. Future research should continue to explore METTL3 targeted therapies and their integrationinto current treatment protocols.^1-5

Works Cited

1.  Shi J, Chen G, Dong X, et al. METTL3 Promotes the Resistance of Glioma to Temozolomide via Increasing MGMT and ANPG in a m6A Dependent
2. Shi J, Zhang P, Dong X, et al. METTL3 knockdown promotes temozolomide sensitivity of glioma stem cells via decreasing MGMT and APNG mRNA stability. Cell Death Discovery. 2023;9(1). doi:https://doi.org/10.1038/s41420-023-01327-y
3. Li F, Chen SY, Yu J, et Interplay of m6A and histone modifications contributes to temozolomide resistance in glioblastoma. Clinical and translational medicine. 2021;11(9). doi:https://doi.org/10.1002/ctm2.553
4. Yin J, Ding F, Cheng Z, et METTL3-mediated m6A modification of LINC00839 maintains glioma stem cells and radiation resistance by activating Wnt/β-catenin signaling. Cell Death & Disease. 2023;14(7). doi:https://doi.org/10.1038/s41419-023-05933-7
5. Oral Administration of STC-15 in Subjects with Advanced Clinicaltrials.gov. Published 2025. Accessed March 26, 2025. https://clinicaltrials.gov/study/NCT05584111?a=6&tab=table