A DNA-replication vulnerability near chromosome centromeres may help explain why reducing ESCO2 made cancer cells more susceptible to PARP-blocking drugs in cell models, researchers at NYU Langone Health said. The study appeared online Thursday, Nov. 5, in Nature Cell Biology under the title “PARP inhibitor cytotoxicity driven by positional replication fork instability.”
CRISPR screens first identified ESCO2 as a factor in drug sensitivity in breast and small-cell lung cancer models, NYU Langone said. Follow-up experiments found that partially reducing the protein also increased sensitivity in colorectal, ovarian and lung cancer cells. ESCO2 helps hold newly copied chromosomes together.
Imaging showed that cells with reduced ESCO2 had more G-quadruplex structures, or G4s, which can obstruct DNA copying. Rather than appearing evenly across the genome, the increase was seen at selected replication sites, especially in repetitive DNA bordering chromosome centromeres, known as pericentromeric regions, the researchers reported.
The response that protects those sites involved PARP1 and the proteins TIMELESS and DDX11, according to NYU Langone. When researchers blocked PARP in ESCO2-reduced cells, G4s accumulated further, DNA synthesis fell and damage increased near centromeres.
PARP inhibitors are used for some breast and ovarian cancers associated with BRCA1 or BRCA2 mutations. Those mutations can impair homologous recombination, a DNA repair process. In the experiments, cells with reduced ESCO2 became more sensitive to the drugs while retaining the homologous-recombination response that researchers tested, suggesting a different route to sensitivity.
The experiments used cancer-cell models, and the results have not established a way to select treatment for patients. NYU Langone said researchers are working with clinicians to study patient-derived cancer cells and investigate potential drug-response biomarkers. The announcement gave no timetable for that work.
NYU Langone said the study was conducted with Pfizer. Six coauthors were Pfizer employees and one was a former employee. Eli Rothenberg, a professor at NYU Grossman School of Medicine's Department of Biochemistry and Molecular Pharmacology, has a laboratory supported by Pfizer, Ionis Pharmaceuticals and the Chang Chavkin Charitable Foundation.
