Mechanism-based design of agents that selectively target drug-resistant glioma.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 35901163.
- Also identified by DOI 10.1126/science.abn7570 and PMC identifier 9502022.
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Abstract
Approximately half of glioblastoma and more than two-thirds of grade II and III glioma tumors lack the DNA repair protein O<sup>6</sup>-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.
Medical subject headings
- Antineoplastic Agents, Alkylating
- Brain Neoplasms
- DNA Modification Methylases
- DNA Repair Enzymes
- Drug Design
- Drug Resistance, Neoplasm
- Glioblastoma
- Tumor Suppressor Proteins