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Review Open Access

Drug resistance in glioblastoma: Challenges, mechanisms and therapeutic strategies (Review)

  • Authors:
    • Yash K. Durga
    • Raju V. Pusapati
  • View Affiliations / Copyright

    Affiliations: Foothill High School, Pleasanton, CA 94588, USA, Cancer Biology, Maipl Therapeutics, Scarsdale, NY 10583, USA
    Copyright: © Durga et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 4
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    Published online on: November 6, 2025
       https://doi.org/10.3892/mco.2025.2913
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Abstract

Glioblastoma multiforme (GBM), the most aggressive and prevalent type of brain cancer, presents a formidable therapeutic challenge due to its high degree of drug resistance. Despite advances in chemotherapy, targeted therapy and immunotherapy, patient outcomes remain dismal, with a 5‑year survival rate of only 7%. Resistance mechanisms are multifactorial, including the restrictive nature of the blood‑brain barrier (BBB), tumor heterogeneity and adaptive responses within the tumor microenvironment (TME). The BBB limits drug delivery, while efflux transporters further reduce therapeutic efficacy. Additionally, the vast molecular genetic and cellular heterogeneity of a glioblastoma enables the survival of resistant subpopulations, such as glioblastoma stem cells, that evade treatment. Chemotherapy resistance in GBM, particularly to temozolomide, is driven by factors such as O6‑methylguanine‑DNA methyltransferase upregulation, defective mismatch repair, hypoxia‑induced gene expression and activation of several signaling pathways, such as the NF‑κB, Hippo and Wnt pathways. Targeted therapies have shown limited success due to activation of compensatory pathways and tumor plasticity, while immunotherapeutic approaches are hindered by an immunosuppressive TME. Recently identified resistance mechanisms, including exosomal transfer of noncoding RNAs and metabolic reprogramming, further complicate treatment. Future directions should emphasize overcoming these challenges through combination therapies, enhanced drug delivery systems and precision medicine approaches. Emerging strategies include targeting persister cells, leveraging metabolic vulnerabilities and integrating AI‑driven drug discovery approaches and nanotechnology. Robust patient stratification and biomarker‑driven interventions are critical for tailoring therapies and improving outcomes. The present review highlights the urgent need for innovative, multidisciplinary approaches to address the complexity of GBM resistance and advance therapeutic strategies for this lethal disease.
View Figures

Figure 1

Root causes of therapeutic resistance
in GBM. Schematic representation of the interconnected mechanisms
that sustain GBM resistance, depicted as a tree where the visible
trunk represents clinical resistance and the hidden root system
illustrates its molecular and cellular drivers. Major resistance
categories are highlighted in red as BBB, IR, TMZ resistance, RR
and TTR. BBB serves as a physical barrier co-opted by the tumor to
reduce drug penetration. Overexpression of efflux transporters such
as P-gp and BCRP in tumor endothelial cells decreases intracellular
drug concentrations, while dysregulation of Wnt and Shh pathways
further limits permeability. IR is reinforced by the highly
immunosuppressive TME, which includes TAMs, GSCs and MDSCs that
suppress cytotoxic T-cell activity. Molecular heterogeneity further
sustains therapy-resistant clones. TMZ resistance is driven by MGMT
upregulation, DNA MMR defects and activation of PI3K/Akt, Hippo and
Wnt/β-catenin pathways. Additional contributors include efflux
transporters, GSCs, a hypoxic TME and exosomal RNAs. TTR reflects
the failure of precision approaches despite subtype-specific
alterations (EGFR in classical, PDGFR in proneural, NF-κB in
mesenchymal GBM). Resistance mechanisms include kinase domain
mutations, RTK coactivation (EGFR, ERBB3, PDGFR, MEK), adaptive
suppression of EGFRvIII and bypass signaling via NF-κB or
IGF1R-PI3K/AKT activation. RR arises from hypoxia, enhanced DDR and
GSC-mediated repair capacity. RTP cells survive through homologous
recombination and non-homologous end joining. Together, these
mechanisms form a deeply interconnected ‘root system’ that allows
GBM to withstand chemotherapy, radiotherapy, targeted therapy and
immunotherapy. This conceptual framework emphasizes that resistance
arises not from a single pathway but from a dynamic, adaptive
network, underscoring the need for rational combination regimens,
precision therapies, and innovative delivery strategies to overcome
therapeutic failure in GBM. GBM, glioblastoma multiforme; BBB,
blood-brain barrier; IR, immunotherapy resistance; TMZ,
temozolomide; RR, radiotherapy resistance; TTR, targeted therapy
resistance; TME, tumor microenvironment; TAM, tumor-associated
macrophage; GSC, glioma stem-like cell; MDSC, myeloid-derived
suppressor cell; MGMT, O6-methylguanine-DNA
methyltransferase; EGFR, epidermal growth factor; MMR, mismatch
repair; PDGFR, platelet-derived growth factor; RTL, receptor
tyrosine kinase; DDR, DNA damage response; RTP, radiation-tolerant
persister; P-gp, P-glycoprotein; BCRP, breast-cancer-resistance
protein; Shh, sonic hedgehog; MEK, mitogen-activated protein
kinase.
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Copy and paste a formatted citation
Spandidos Publications style
Durga YK and Pusapati RV: Drug resistance in glioblastoma: Challenges, mechanisms and therapeutic strategies (Review). Mol Clin Oncol 24: 4, 2026.
APA
Durga, Y.K., & Pusapati, R.V. (2026). Drug resistance in glioblastoma: Challenges, mechanisms and therapeutic strategies (Review). Molecular and Clinical Oncology, 24, 4. https://doi.org/10.3892/mco.2025.2913
MLA
Durga, Y. K., Pusapati, R. V."Drug resistance in glioblastoma: Challenges, mechanisms and therapeutic strategies (Review)". Molecular and Clinical Oncology 24.1 (2026): 4.
Chicago
Durga, Y. K., Pusapati, R. V."Drug resistance in glioblastoma: Challenges, mechanisms and therapeutic strategies (Review)". Molecular and Clinical Oncology 24, no. 1 (2026): 4. https://doi.org/10.3892/mco.2025.2913
Copy and paste a formatted citation
x
Spandidos Publications style
Durga YK and Pusapati RV: Drug resistance in glioblastoma: Challenges, mechanisms and therapeutic strategies (Review). Mol Clin Oncol 24: 4, 2026.
APA
Durga, Y.K., & Pusapati, R.V. (2026). Drug resistance in glioblastoma: Challenges, mechanisms and therapeutic strategies (Review). Molecular and Clinical Oncology, 24, 4. https://doi.org/10.3892/mco.2025.2913
MLA
Durga, Y. K., Pusapati, R. V."Drug resistance in glioblastoma: Challenges, mechanisms and therapeutic strategies (Review)". Molecular and Clinical Oncology 24.1 (2026): 4.
Chicago
Durga, Y. K., Pusapati, R. V."Drug resistance in glioblastoma: Challenges, mechanisms and therapeutic strategies (Review)". Molecular and Clinical Oncology 24, no. 1 (2026): 4. https://doi.org/10.3892/mco.2025.2913
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