Chemo-sensitizing IDH1-mutated glioma by molecular targeting

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

We have established a genome-scale chemogenomic screening platform to identify therapeutic vulnerabilities in cellular models that recapitulate distinct molecular subtypes of human glioma. Through this approach, we identified PKMYT1 as a key hallmark of therapy resistance, functioning by reprogramming cell cycle timing to facilitate DNA repair and detoxification. Mechanistic studies revealed that PKMYT1 regulates the G2/M checkpoint by acting on CDK1. Notably, pharmacological inhibition of PKMYT1 synergized strongly with standard glioma chemotherapeutics, leading to improved disease outcomes. In parallel, we uncovered defects in the DNA repair pathway in IDH1-mutant glioma. Our work demonstrated that DNA methylation at damage sites plays an essential role in disrupting homologous recombination repair by impairing CTCF-mediated chromatin organization and conformation adjustment.