Mechanisms of temozolomide resistance in glioblastoma - a comprehensive review

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 firstchoice 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.

Targeting RTK-PI3K-mTOR Axis in Gliomas: An Update

“…Unfortunately, over 50% of GBM patients treated do not respond to the therapy, likely due to the highly heterogeneous and mutation-prone nature of GBM (oppure glioblastoma vs. temozolomide: Can the red queen race be won?). It is also quite common for these tumors to develop resistance to TMZ, which can either be an inherent characteristic or acquired after initial treatment [ 48 ]. As TMZ resistance is a clinically meaningful obstacle that must be overcome for the successful treatment of GBM, an in-depth understanding of the molecular mechanisms (and of the cellular populations) that drive resistance is needed.…”

“…As TMZ resistance is a clinically meaningful obstacle that must be overcome for the successful treatment of GBM, an in-depth understanding of the molecular mechanisms (and of the cellular populations) that drive resistance is needed. In addition to the activity of DNA repair enzymes, the dysregulation of specific molecular pathways contributes to TMZ resistance [ 48 ]. Among these altered pathways, alterations of RTKs, including their genetic mutations or an abnormal expression, have been involved in drug resistance in CNS tumors.…”

Identification of Differentially Expressed Genes in Different Glioblastoma Regions and Their Association with Cancer Stem Cell Development and Temozolomide Response

“…Regarding TMZ resistance in GBM treatment, several conclusions in related studies have been based on GBM cell lines with previously understood responses to TMZ (resistance or sensitivity) [32,40]. However, those results were limited to real situations in which tumor tissue was able to resist TMZ treatment through the actions of multiple pathways [41]. In most patients, their recurrent GBM is resistant to TMZ treatment, which is the first-line chemotherapeutic agent for this disease [42].…”

“…Eleven common upregulated genes in high-risk groups among different data cohorts were recognized as potential biomarkers of TMZ resistance in primary GBM. Some were suggested to be involved in relevant pathways that could affect TMZ responses [41]. For example, ARID5A deficiency could decrease ROS generation, thus modulating autophagy [43].…”

Anticancer Potential of Temozolomide-Loaded Eudragit-Chitosan Coated Selenium Nanoparticles: In Vitro Evaluation of Cytotoxicity, Apoptosis and Gene Regulation

“…This process ensues during DNA replication by carrying a methyl group that attaches to guanine at the O6 and N7 positions, and adenine at the N3 position. These mismatched lethal base pairs can result in single- and double-strand DNA breaks (DSB) that lead to cell apoptosis [ 5 , 6 ]. TMZ is a class of imidazotetrazines [ 7 , 8 , 9 ] that is an alkylating agent, which is stable at acidic pH but is rapidly converted to 3- methyl-(traiazan-1-yl) imidazole- 4- carboxamide (MTIC) at physiological pH [ 7 , 8 ].…”