Keywords
Temozolomide
Chemoresistance
Glioma stem cells
Tumor microenvironment
Precision therapy
Biomarkers
How to Cite
Abstract
Glioblastoma (GBM) is the most prevalent and lethal diffuse glioma in adults and is still linked with fast functional deterioration and a median overall survival of ~1–1.5 years after maximal safe resection and radiotherapy with concomitant and adjuvant temozolomide (TMZ). Although TMZ induces O6-methylguanine lesions in DNA, chemotherapy resistance is very heterogeneous and clinically unsolved. However, radiotherapy is only effective because the disease can recur after treatment, which means that no single biomarker (like methylation of the MGMT promoter) can account for radiotherapy resistance. The goal of this narrative review was to understand and emerging clinical mechanisms of resistance to TMZ into a multi-dimensional context for supporting biomarker strategies, patient stratification and mechanism-driven precision therapies. The PubMed and Google Scholar databases were searched to find all relevant review articles, preclinical and clinical cohort studies of TMZ resistance in glioma and these were grouped into DNA repair (MGMT, mismatch repair [MMR], base excision repair [BER]), tumor microenvironment/blood–brain barrier (BBB), signaling pathways, non-coding RNAs/epigenetics, metabolism/redox biology and therapeutic approaches, and narratively synthesized. TMZ resistance seems to occur in a multifactorial and interactive manner: MGMT activity has been found to reverse TMZ damage and methylation of MGMT is not a dichotomous predictor, but a graded one, with intermediate methylation showing a modest benefit, and intensive therapy having an impact on the survival difference between methylated and unmethylated TMZ resistant tumors. The MMR defects that occur after birth (such as MSH6/MLH1) promote the selection of TMZ and hypermutator recurrence, and BER (including APNG upregulation) can confer resistance even in the presence of MGMT-methylation. Common mechanisms of resistance to glioblastoma treatment include metabolic and epigenetic changes, stress response pathways, non-coding RNAs, intratumoral heterogeneity, and microenvironmental factors, such as BBB-related drug exclusion and immunosuppressive cytokines. The use of clinical strategies against MGMT or immune checkpoints has been ineffective, possibly because of drug toxicity and delivery. There is current evidence for the value of integrated multi-omics profiling, as well as better delivery systems and combination therapies aimed at different resistance pathways to prevent recurrence.
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