Mechanism-based design of agents that selectively target drug-resistant glioma.
Kingson LinSusan E GuebleRanjini K SundaramEric D HusemanRanjit S BindraSeth B HerzonPublished in: Science (New York, N.Y.) (2022)
Approximately half of glioblastoma and more than two-thirds of grade II and III glioma tumors lack the DNA repair protein O 6 -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.
Keyphrases
- dna repair
- drug resistant
- dna damage
- cell death
- dna methylation
- dna damage response
- multidrug resistant
- acinetobacter baumannii
- small molecule
- oxidative stress
- single cell
- high grade
- gene expression
- cell therapy
- cell free
- cystic fibrosis
- signaling pathway
- mesenchymal stem cells
- single molecule
- pseudomonas aeruginosa
- circulating tumor
- cell proliferation