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Sharma et al. Cancer Drug Resist 2023;6:688-708 https://dx.doi.org/10.20517/cdr.2023.82 Page 690

Enhanced DNA damage repair pathways (MGMT) and abnormal activation of survival signaling
pathways
As part of the glioblastoma standard treatment regimen, TMZ is a potent DNA alkylating agent that leads to
DNA damage in cancer cells and cell death . However, TMZ treatment often results in drug resistance in
[30]
~50% of glioblastoma patients due to overexpression of MGMT, which reverses the methylation of the O6
position of guanine. In addition to upregulated MGMT expression, glioblastoma often exhibits enhanced
DNA damage repair capacity through several related mechanisms. For instance, poly(ADP-ribose)
polymerase (PARP) was shown to interact with MGMT and enhance MGMT function in the removal of
O6-methylation of DNA . Interestingly, even in MGMT-deficient glioblastoma, TMZ resistance may still
[31]
arise due to the loss of mismatch repair (MMR) pathway in tumor cells. Recent work by Lin et al. developed
a new class of compound (KL-50) to achieve MMR-independent glioblastoma cell killing. It demonstrated a
promising strategy to exploit cancer-specific deficiencies in DNA repair pathways . Glioblastoma tumors
[32]
also have elevated levels of receptor tyrosine kinases, such as EGFR gene amplification or mutation
(EGFRvIII), PDGFR and FGFR, and aberrant activation of PI3K/ATK signaling and other growth factors
(e.g., IGF-1, CTGF, and TGFβ) [33-39] , with a potential contribution to the drug resistance phenotype.

Role of glioma stem cells
Glioma stem cells (GSCs) represent a subpopulation of relatively undifferentiated cells capable of self-
renewal while also generating clonal populations of differentiated tumor cells in glioblastoma. These cells
are increasingly recognized as a driving force supporting glioma genesis, therapy resistance, and
recurrence . GSCs have high regenerative capacity and can differentiate into cells expressing several
[40]
lineage markers such as CD133, SOX2, CD15, CD44, integrin α6, and CD36 . Along with heterogeneity,
[41]
various factors contribute to the chemoresistance of GSCs. Intrinsic factors include upregulated MGMT,
higher anabolic capacity, and autophagy-mediated clearance of ROS induced by chemotherapy. Extrinsic
factor is mainly hypoxic tumor microenvironment (TME). Hypoxia promotes the expression of GSC
markers and a cancer stem-like phenotype . Hypoxia-response genes, such as hypoxia-inducible factor
[42]
HIF-2α and VEGF, are highly expressed in GSCs. Intriguingly, two reports have demonstrated that hypoxia-
associated transcriptional signatures can be used as prognostic markers for glioblastoma patients [43,44] .

Epigenetic modulations
Epigenetic dysregulation has been increasingly recognized as one of the significant drivers of oncogenesis,
and several subtypes of glioblastoma are associated with epigenetic alterations [45,46] . These epigenetic
modifications may serve as valuable biomarkers for tumor stratification and prognostic prediction. For
instance, the glioblastoma resistance to receptor tyrosine kinase (RTK) inhibitors has been found to involve
both genetic and epigenetic mechanisms , resulting in subclones with a gain of copy number in the insulin
[47]
receptor substrate-1(IRS1) and substrate-2 (IRS2) loci. Another study identified a long non-coding RNA
(LINC00021) that promotes TMZ resistance through Notch signaling and epigenetically silenced p21
expression via recruiting EZH2 , one of the methyltransferases responsible for histone methylation.
[48]
Epigenetic modifications in glioblastoma are also exploited as drug targets. Among the promising epigenetic
interventions for glioblastoma are the histone deacetylase (HDAC) inhibitors , which have been
[49]
extensively tested in various cancers . HDAC inhibitors can block cancer cell proliferation by inducing cell
[50]
cycle arrest, cell differentiation, and/or apoptosis . With a large amount of supportive preclinical data,
[51]
various HDAC inhibitors in glioblastoma clinical trials are underway.

DRUG RESISTANCE TO IMMUNOTHERAPY IN GLIOBLASTOMA
Current status of immunotherapy trials in glioblastoma
Although immune checkpoint inhibitors have greatly improved cancer treatment today, the clinical trials in
glioblastoma treatment have been largely unsuccessful.