Genotoxic therapy and resistance mechanism in gliomas

Abstract

Glioma is one of the most common and lethal brain tumors. Surgical resection followed by radiotherapy plus chemotherapy is the current standard of care for patients with glioma. The existence of resistance to genotoxic therapy, as well as the nature of tumor heterogeneity greatly limits the efficacy of glioma therapy. DNA damage repair pathways play essential roles in many aspects of glioma biology such as cancer progression, therapy resistance, and tumor relapse. O6-methylguanine-DNA methyltransferase (MGMT) repairs the cytotoxic DNA lesion generated by temozolomide (TMZ), considered as the main mechanism of drug resistance. In addition, mismatch repair, base excision repair, and homologous recombination DNA repair also play pivotal roles in treatment resistance as well. Furthermore, cellular mechanisms, such as cancer stem cells, evasion from apoptosis, and metabolic reprogramming, also contribute to TMZ resistance in gliomas. Investigations over the past two decades have revealed comprehensive mechanisms of glioma therapy resistance, which has led to the development of novel therapeutic strategies and targeting molecules.

Trial registration: ClinicalTrials.gov NCT03572530 NCT02332889 NCT02940483 NCT01817751 NCT03048084.

Keywords: Cancer; Genotoxic therapy; Glioma; Therapy resistance.

Conflict of interest statement

Declaration of Competing Interest The authors declare no competing financial interests.

Published by Elsevier Inc.

Figures

Figure 1.. TMZ induced DNA damage repair

TMZ is hydrolyzed to its active metabolite, 3-methyl-(triazen-1-yl) imidazole-4-carboxamide (MTIC), and then splits into monomethyl diazonium ions and 5-aminoimidazole-4-carboxamide (AIC). TMZ causes methyl adducts specifically at the N1-methyladenine (N1meA) and N3-methylcytosine (N3meC) (2%); N7-methylguanine (N7-meG) (80%–85%); N3-methyladenine (N3-meA) or N3-methylguanine (N3-meG) (8%), and O6-methylguanine (O6-meG) (8%). ALKBH2 and ALKBH3 remove N1meA and N3meC, accompanying with oxidative decarboxylation of 2-oxoglutarate (α-ketoglutarate, αKG) to succinate (Suc). MGMT is responsible for repairing O6-meG lesions. MGMT transfers the methyl group from O6-meG to its cysteine residue, resulting in the methylation and degradation of itself. If O6-meG adducts fail to be removed by MGMT, it will mispair with thymine. O6-meG-T mismatches are recognized by MMR components MSH2 and MSH6. MMR components MLH1 and PMS2 further removes the thymine residue and leave the O6-meG adduct unrepaired. The futile repair cycles lead to the accumulation of DNA strand breaks and eventually apoptosis. N7-meG and N3-meA adducts account for about 80% of TMZ-induced DNA adducts. BER system efficiently fixes these lesions. MPG is responsible for the detection and removal of aberrantly N7-meG and N3-meA. APE recognizes the abasic site, cleaves the 5’ end of the DNA, and triggers PARP1 to undergo patch repair. Patch repair can be completed by DNA polymerase, DNA ligase III, and XRCC1 (short patch) or FEN1 and DNA ligase I (long patch).

Figure 2.. TMZ induced double strands breaks addressed by Homologous Repair

Unrepaired O6-meG adducts will lead to DSB, which is the most lethal DNA damage. DSB can be sensed by the MRE11-RAD50-NBS1 (MRN complexes), which set in motion a numbers of processes collectively called the DNA damage response to coordinate DNA repair, These sensor complexes recruit and activate kinases including ATM, ATR, DNA-PK and subsequently other modifying enzymes which, through cascades of phosphorylation and ubiquitination events, activate and mobilize a large number of proteins, such as p53, BRCA1, 53BP1 and H2AX. Homologous Repair requires resection by BRCA1, CtIP and BARD1 to generate single-stranded DNA (ssDNA), which immediately becomes coated by RPA and subsequently replaced by Rad51 preparing for strand invasion. Failure of Homologous Repair will result in cell death.