Temozolomide Resistance in Glioblastoma Multiforme: Mechanisms, Ramifications, and Potential Solutions to an Urgent Clinical Problem

Glioblastoma multiforme (GBM) is the most common and malignant type of brain cancer. Current standard therapy for GBM involves surgery followed by ionizing radiation and treatment with temozolomide (TMZ), a DNA-alkylating agent. At the molecular level, TMZ produces several distinct DNA lesions such as N7 -methylguanine, N3 -methyladenine, and O6 -methylguanine that all produce cytostatic and cytotoxic effects against GBM cells. The unique molecular nature of each lesion requires that cells utilize several mutually exclusive DNA repair pathways to effectively correct the DNA damage inflicted by TMZ. At face value, the diversity in DNA repair pathways suggests that drug resistance to TMZ would be a relatively rare occurrence after treatment. Unfortunately, this is not the case. While TMZ treatment does extend post-operative survival by several months, most patients develop resistance to this anti-cancer agent which significantly reduces overall survival. This review assesses this important clinical problem by examining the molecular and cellular mechanisms responsible for the anti-cancer activity of TMZ as well as the mechanisms associated with inherent and TMZ-induced drug resistance.

Keywords: Glioblastoma multiforme; DNA damage; Chemotherapy; Drug resistance; DNA repair; Mutagenesis

Abbreviations: GBM: glioblastoma multiforme; TMZ: temozolomide; EGFR: epidermal growth factor receptor; LOH: loss of heterozygosity; PTEN: phosphatase and tensin homolog; IR: ionizing radiation; OS: overall survival; BCNU: 1,3-bis(2-chloroethyl)-1-nitrosourea; DOX: doxorubicin; MMR: mismatch DNA repair; MGMT: O⁶ -methylguanine methyltransferase; BER pathway: base excision repair; TLS: translesion DNA synthesis; NFκB: nuclear factor kappa B; EGFRvIII: epidermal growth factor receptor variant III; NER: nucleotide excision repair; HR: homologous recombination; DSBs: double-strand breaks; SSBs: single-strand breaks; AAG: alkylpurine-DNA-N-glycosylase; 5’-dRP: 5′ deoxyribose phosphate; PARP1: poly (ADPribose) polymerase 1; Akt-mTOR: mammalian target of rapamycin; pol η: polymerase eta; pol ɩ: polymerase iota; pol Ѳpolymerase theta; pol : polymerase zeta; pol κ: polymerase kappa; pol α: polymerase alpha; pol δ: polymerase delta; pol ε: polymerase epsilon; pol γ: polymerase gamma; pol β: polymerase beta; pol λ: polymerase lambda; pol μ: polymerase mu; TdT: terminal deoxynucleotidyl transferase; RTPCR: reverse transcriptase polymerase chain reaction; 5-NITP: 5-nitroindolyl-2’-deoxyribonucleoside triphosphate; 5-NIdR: 5-nitroindolyl-2’-deoxyribonucleoside; MTD: median time for death