Genotoxic therapy and resistance mechanism in gliomas

Pharmacol Ther. 2021 Dec:228:107922. doi: 10.1016/j.pharmthera.2021.107922. Epub 2021 Jun 23.

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.

Publication types

  • Research Support, N.I.H., Intramural
  • Review

MeSH terms

  • Brain Neoplasms* / drug therapy
  • Brain Neoplasms* / genetics
  • DNA Damage / drug effects
  • Glioma* / drug therapy
  • Glioma* / genetics
  • Humans

Associated data

  • ClinicalTrials.gov/NCT03572530
  • ClinicalTrials.gov/NCT02332889
  • ClinicalTrials.gov/NCT02940483
  • ClinicalTrials.gov/NCT01817751
  • ClinicalTrials.gov/NCT03048084