Mechanism-based design of agents that selectively target drug-resistant glioma

Science. 2022 Jul 29;377(6605):502-511. doi: 10.1126/science.abn7570. Epub 2022 Jul 28.


Approximately half of glioblastoma and more than two-thirds of grade II and III glioma tumors lack the DNA repair protein O6-methylguanine methyl transferase (MGMT). MGMT-deficient tumors respond initially to the DNA methylation agent temozolomide (TMZ) but frequently acquire resistance through loss of the mismatch repair (MMR) pathway. We report the development of agents that overcome this resistance mechanism by inducing MMR-independent cell killing selectively in MGMT-silenced tumors. These agents deposit a dynamic DNA lesion that can be reversed by MGMT but slowly evolves into an interstrand cross-link in MGMT-deficient settings, resulting in MMR-independent cell death with low toxicity in vitro and in vivo. This discovery may lead to new treatments for gliomas and may represent a new paradigm for designing chemotherapeutics that exploit specific DNA repair defects.

MeSH terms

  • Antineoplastic Agents, Alkylating* / chemistry
  • Antineoplastic Agents, Alkylating* / pharmacology
  • Antineoplastic Agents, Alkylating* / therapeutic use
  • Brain Neoplasms* / drug therapy
  • Brain Neoplasms* / genetics
  • Cell Line, Tumor
  • DNA Methylation / genetics
  • DNA Modification Methylases* / genetics
  • DNA Repair / genetics
  • DNA Repair Enzymes* / genetics
  • Dacarbazine / pharmacology
  • Dacarbazine / therapeutic use
  • Drug Design*
  • Drug Resistance, Neoplasm* / genetics
  • Glioblastoma* / drug therapy
  • Glioblastoma* / genetics
  • Humans
  • Temozolomide / pharmacology
  • Temozolomide / therapeutic use
  • Tumor Suppressor Proteins* / genetics


  • Antineoplastic Agents, Alkylating
  • Tumor Suppressor Proteins
  • Dacarbazine
  • DNA Modification Methylases
  • MGMT protein, human
  • DNA Repair Enzymes
  • Temozolomide