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. 2021;4(1):17-43.
doi: 10.20517/cdr.2020.79. Epub 2021 Mar 19.

Mechanisms of temozolomide resistance in glioblastoma - a comprehensive review

Neha Singh  1   2 , Alexandra Miner  1   2 , Lauren Hennis  1   2 , Sandeep Mittal  1   2   3
Affiliations

Mechanisms of temozolomide resistance in glioblastoma - a comprehensive review

Neha Singh et al. Cancer Drug Resist. 2021.

Abstract

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and has an exceedingly low median overall survival of only 15 months. Current standard-of-care for GBM consists of gross total surgical resection followed by radiation with concurrent and adjuvant chemotherapy. Temozolomide (TMZ) is the first-choice chemotherapeutic agent in GBM; however, the development of resistance to TMZ often becomes the limiting factor in effective treatment. While O6-methylguanine-DNA methyltransferase repair activity and uniquely resistant populations of glioma stem cells are the most well-known contributors to TMZ resistance, many other molecular mechanisms have come to light in recent years. Key emerging mechanisms include the involvement of other DNA repair systems, aberrant signaling pathways, autophagy, epigenetic modifications, microRNAs, and extracellular vesicle production. This review aims to provide a comprehensive overview of the clinically relevant molecular mechanisms and their extensive interconnections to better inform efforts to combat TMZ resistance.

Keywords: Glioblastoma; chemoresistance; molecular mechanisms; temozolomide.

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Conflict of interest statement

Conflicts of interest All authors declared that there are no conflicts of interest.

Figures

Figure 1
Figure 1
The role of glioma stem cells (GSCs) in tumorigenesis. The heterogeneous nature of glioblastoma (GBM) tumors creates an opportunity for the evolutionary selection of particular clonal cell populations with growth advantages and propagates advantageous mutations. In particular, a small population of quiescent cells with stem-like properties, GSCs, has been shown to be particularly resistant to temozolomide treatment in GBM and these cells are thought to act as the recurrent tumor-initiating cells, which are responsible for regrowth of tumors after initial treatment. While the criteria for defining GSCs are still evolving, the most commonly used markers for GSCs include CD133+, CD44+, CD15+, CD70+, S100A4, ALDH1A3, Nanog, SOX-2, and Nestin. These stem cell characteristics are enhanced by many of the molecular mechanisms of temozolomide resistance in GBM as well as being intrinsic drivers of resistance. Modified from Xie et al.[28]
Figure 2
Figure 2
Mechanism of TMZ metabolism, DNA damage and DNA repair. Under physiological conditions TMZ is metabolized to MTIC and then to its active form, a methyl diazonium ion. The electrophilic methyl diazonium ion acts as a methyl donor, transferring its methyl group to negatively charged DNA and creating DNA adducts. This alkylating activity occurs preferentially at N7 of guanine, O3 of adenine and O6 of guanine and, if left unrepaired, results in improper base pairing and single and double-stranded DNA breaks. The primary endogenous DNA repair mechanisms that counteract the DNA damage caused by TMZ, and are thus commonly implicated in TMZ resistance, include MGMT, BER and MMR. TMZ: temozolomide; MTIC: metabolite 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide; MGMT: O6-methylguanine-DNA methyltransferase; BER: base excision repair; MMR: mismatch repair
Figure 3
Figure 3
Molecular pathways associated with TMZ resistance. In the RTK pathway, activation of RTK results in downstream signaling controlling cell survival or apoptosis. Amplification of EGFR and inclusion of the mutant variant EGFRvIII, both RTKs, occurs in a majority of GBM. EGFRvIII has been shown to be a constitutively active mutant of EGFR, with ligand-independent activation resulting in RTK/RAS/PI3 dysregulation. Modified from Pearson et al.[63]. TMZ: temozolomide; RTKs: receptor tyrosine kinases; EGFR: epidermal growth factor receptor; EGFRvIII: epidermal growth factor receptor variant III
Figure 4
Figure 4
Wnt/β-catenin signaling pathways. In the canonical (β-catenin-dependent) pathway, Wnt ligand binds to its Frizzled receptor and co-receptor LRP 5/6. Upon activation, the signal is transduced and DVL1 gets activated which in turn inhibits GSK-3β and CK1 activity. This inhibition results in accumulation of intracellular β-catenin and its translocation into the nucleus. β-catenin acts as a transcriptional regulator along with LEF1 and TCF4. This transcriptional complex induces the expression of Wnt target genes that promote cell proliferation and differentiation. In the non-canonical (β-catenin-independent) pathway, Wnt ligands binds to its Frizzled receptor and triggers DLV1 to activate the cGMP-specific PDE and PLC. Activated PLC cleaves the membrane-bound PIP2 into IP3 and DAG. IP3 induces intracellular Ca2+ release from the endoplasmic reticulum. The resulting Ca2+ activates both CaMKII and calcineurin. CaMKII activates transcription factor NF-κB and calcineurin activates transcription factor NFAT. Cytoplasmic levels of β-catenin are kept low by downstream kinases of calcineurin NLK and TAK1. Modified from Tompa et al.[92]
Figure 5
Figure 5
Mechanisms of resistance through TMZ-induced autophagy. Pathway #1: Endoplasmic reticulum (ER) stress triggers the unfolded protein response; downstream factors including IRE1 activate XBP1 and molecules downstream of JNK. Pathway #2: Accumulation of reactive oxygen species (ROS) results in activation of the MAP/ERK pathway. Pathway #3: Activation of ATM/AMPK pathway. Pathway #4: Activation of P13K/AKT pathway. Pathway #5. Activation of JAK2/STAT3 pathway. Modified from Hombach-Klonisch et al.[145]. TMZ: temozolomide
Figure 6
Figure 6
Role of miRNA in GBM tumorigenesis. MicroRNAs exert their effects by binding and interacting with their target mRNA, resulting in degradation or translational repression of the target protein. Due to their function, miRNAs effectively function as either oncogenic miRNA or tumor suppressive mRNA. miRNAs are oncogenic when their target proteins are tumor suppressors; conversely, miRNAs are tumor suppressive when their target proteins are oncogenic. The downregulation of tumor suppressor proteins and upregulation of oncogenic proteins can cause an increase in cancer stemness, promote cell proliferation, angiogenesis and invasion and inhibit apoptosis. Through these mechanisms, miRNAs play a key role in chemoresistance. Modified from Mizoguchi et al.[197]. GBM: glioblastoma
Figure 7
Figure 7
Overview of mechanisms involved in TMZ resistance in GBM. The molecular mechanisms contributing to TMZ resistance in GBM are nuanced and extensive yet fall primarily into the fundamental categories of DNA repair, cell stemness, HDAC activity, aberrant receptor and transcription factor activity, autophagy, activation and suppression by various miRNAs, and intercellular transport of oncogenic factors via extracellular vesicles. There is significant interplay between all of these categories, and often a mutation or overactivation in one category will prompt or amplify additional resistance pathways. For this reason, successful combating of TMZ resistance will require a multifaceted approach that prevents compensation through alternative resistance mechanisms. GBM: glioblastoma; TMZ: temozolomide; HDACs: histone deacetylases
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References

    1. Ostrom QT, Cioffi G, Gittleman H, et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2012-2016. Neuro Oncol. 2019;21:v1–100. doi: 10.1093/neuonc/noz150. - DOI - PMC - PubMed
    1. Krex D, Klink B, Hartmann C, et al. Long-term survival with glioblastoma multiforme. Brain. 2007;130:2596–606. doi: 10.1093/brain/awm204. - DOI - PubMed
    1. Johnson DR, O’Neill BP. Glioblastoma survival in the United States before and during the temozolomide era. J Neurooncol. 2012;107:359–64. doi: 10.1007/s11060-011-0749-4. - DOI - PubMed
    1. Delgado-Lopez PD, Corrales-Garcia EM. Survival in glioblastoma: a review on the impact of treatment modalities. Clin Transl Oncol. 2016;18:1062–71. doi: 10.1007/s12094-016-1497-x. - DOI - PubMed
    1. Stupp R, Brada M, van den Bent MJ, et al. High-grade glioma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25 Suppl 3:iii93–101. doi: 10.1093/annonc/mdu050. - DOI - PubMed

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