Mechanisms of temozolomide resistance in glioblastoma - a comprehensive review

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.

Automated summary

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with a low median overall survival. Current standard treatment includes surgery followed by radiation and chemotherapy, with temozolomide (TMZ) being the first-choice chemotherapy drug. However, the development of resistance to TMZ is a major challenge in effective treatment, with multiple molecular mechanisms contributing to this resistance, such as DNA repair systems, signaling pathways, autophagy, epigenetic modifications, and microRNAs.