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Page 689 Sharma et al. Cancer Drug Resist 2023;6:688-708 https://dx.doi.org/10.20517/cdr.2023.82

the most common type of primary brain tumor . Glioblastoma is a grade IV astrocytoma that was initially
[1]
categorized into four molecular subtypes, termed neural, proneural, classical, and mesenchymal subtype .
[2]
Transcriptional profiling and genetic modeling in mice showed that glioblastoma originated from neural
stem cells (NSC), NSC-derived astrocytes, and oligodendrocyte precursor cells (OPCs) . Besides the four
[3-5]
molecular subtypes based on their transcription profiling, glioblastoma tumors can also be classified by the
status of the isocitrate dehydrogenase gene (IDH) as IDH wild-type and IDH-mutant tumors. Similarly,
epigenetics factors, such as CpG island methylation phenotype of O6-methylguanine-DNA
methyltransferase (MGMT) promoter, are also commonly used for glioblastoma tumor stratification .
[6,7]

Since the approval of Temozolomide (TMZ) for newly diagnosed glioblastoma treatment by the FDA in
early 2000, surgery followed by radiotherapy and TMZ treatment has remained the first-line glioblastoma
treatment . However, none of these therapies eliminate cancer cells entirely because of challenges marred
[8]
by high infiltration rate, tumor heterogeneity, blood-brain barrier (BBB), and immunosuppressive
environment factors [9,10] . The highly infiltrative nature of glioblastoma does not allow the removal of
cancerous cells using resection; self-renewing cells followed by resection become more prone to
radioresistance and chemoresistance. Similarly, cellular heterogeneity and BBB prevent targeted drug
delivery in glioblastoma [11,12] .

COMMON DRUG RESISTANCE MECHANISMS IN BRAIN CANCERS
Blood-brain barrier
Although the BBB in glioblastoma is compromised to some extent, tumor BBB still presents a great
challenge for therapeutics to reach glioblastoma cells. As the intrinsic barrier for brain cancer, BBB is a
microvasculature structure surrounding the central nervous system (CNS), tightly regulating the movement
of molecules and cells between the CNS and blood. Normally, BBB maintains the homeostasis of CNS and
prevents infiltration of toxins, pathogens, inflammation, and harmful metabolites [13-15] . Disruption of the
neurovascular unit (NVU) is associated with blood-brain dysfunction in neurodegenerative disease and
brain tumors . The NVU consists of vascular cells (endothelial, pericytes, and vascular smooth muscle
[16]
cells), glia (astrocytes, microglia, and oligodendroglia), and neurons, and it plays an important role in
maintaining BBB functional integrity and regulating the volume of cerebral blood flow [17,18] . The endothelial
cells in neurovascular parenchyma form capillary beds connected through tight junctions (TJs), surrounded
by a specialized basal lamina shared with pericytes and astrocytic end feet. They are sparsely interconnected
by neuronal endings and microglia [19,20] . Astrocytes and pericytes, an essential constituent of NVU, release
Sonic Hedgehog and vitronectin and angiopoietin I, respectively, acting on endothelial cells for their
survival and maintaining BBB.

Overexpression of efflux pumps
Efflux transporters on the BBB membrane also contribute to cerebrospinal fluid homeostasis by protecting
it from potentially harmful endogenous and exogenous substances [21,22] . These transporters also pose
challenges by blocking therapeutic compounds from entering the brain parenchyma. Efflux transporters on
compartments of the BBB belong to either ATP-binding cassette (ABC) or the solute carrier (SLC)
superfamilies [23,24] . Organic anion-transporting polypeptides (OATP) are a superfamily of solute carrier
organic anionic (SLCO) transmembrane transporters that are known for cancer drug resistance [25,26] . These
peptide transporters regulate a variety of xenobiotic and endogenous substrates, including endogenous
hormones, their conjugates, and anticancer drugs . OATP1A2 is a sodium-independent uptake transporter
[27]
family member and is highly expressed on the luminal membrane of BBB in tumors and adjacent healthy
tissues . A study by Cooper et al. in glioblastoma patients showed significant over-expression of all the
[28]
OATP isoforms (OATP1A2, 2B1, 1C1, and 4A1) in tumor tissues compared to non-neoplastic brain .
[29]