Advanced Imaging Uncovers Genomic Achilles' Heel That Makes Cancer Cells Vulnerable to Treatment

NEW YORK, Nov. 5, 2026 /PRNewswire/ -- A small subset of vulnerable DNA sites can make cancer cells highly sensitive to targeted drugs called PARP inhibitors, a new study shows.

Led by researchers at NYU Langone Health and its Perlmutter Cancer Center, the work revolved around failures of DNA to copy itself at certain sites in genetic chains, which it must do for cells to divide and multiply as part of healing and growth. Cancerous cells depend on protective mechanisms that have evolved to overcome these failures when they are triggered by cancer drugs.

Published in Nature Cell Biology online November 5, the study reveals how DNA replication failures at critical sites in chromosomes, the protein superstructures that house and provide access to DNA, determine how vulnerable cancer cells are to PARP inhibitors.

The research team pinpointed replication problems at critical chromosome regions and identified the protective response that keeps DNA replication failures in check. Blocking that protective response let localized damage caused by cancer treatments build up, compromising the cancer cells' survival.

The discovery reveals how the location of DNA damage can shape treatment response and provides a foundation for developing new biomarkers of cancer drug sensitivity.

"We often think of DNA damage in terms of quantity: More damage means a greater chance of killing a cancer cell," said co-corresponding author Eli Rothenberg, PhD, a professor in the Department of Biochemistry and Molecular Pharmacology at NYU Grossman School of Medicine. "Our work reveals a genomic Achilles' heel—a small subset of sites where replication problems can have disproportionately severe consequences. Identifying those sites helps explain what cancer cells depend on to survive and why a particular treatment can be so effective."

Understanding which replication problems create a dependence on a particular protective pathway to fix them requires researchers to detect the underlying molecular events. The researchers identified these vulnerable sites using ultrasensitive molecular imaging enabled by advanced microscopy methods and technologies developed in Dr. Rothenberg's laboratory.

These approaches are particularly powerful because they reveal distinct molecular events within cells, including subtypes of replication-associated damage sites that other methods cannot readily distinguish, said Dr. Rothenberg. This enabled the researchers to pinpoint where problems arise and how cells respond.

The current study focused on ESCO2, a protein that helps establish the connections holding newly copied chromosomes together. CRISPR screens in breast and small cell lung cancer models identified ESCO2 as a strong determinant of sensitivity to PARP inhibitors. Follow-up experiments showed that even partial reduction of ESCO2 increased sensitivity to PARP inhibitors in colorectal, ovarian, and lung cancer cells.

PARP inhibitors are used to treat some cancers, including certain breast and ovarian cancers with mutations in BRCA1 or BRCA2. These mutations can impair homologous recombination, an important DNA repair process. ESCO2-depleted cells, however, became sensitive to PARP inhibitors while retaining the tested homologous recombination response, prompting the researchers to investigate what created their dependence on PARP activity.

The imaging in the new study revealed that reducing ESCO2 increased unusual, folded DNA structures called G-quadruplexes, or G4s, which can obstruct DNA copying. The increased burden was concentrated at a small subset of replication sites. Particularly vulnerable sites lay in repetitive stretches of DNA bordering centromeres called pericentromeric regions, which help ensure that chromosomes are distributed correctly during cell division.

"The imaging enabled us to move beyond measuring damage across an entire cell," said Dipika Gupta, PhD, the study's first and co-corresponding author and a postdoctoral scholar in Dr. Rothenberg's laboratory. "We could detect subtle replication problems, distinguish the sites involved, and identify the protective response that the cells relied on. That revealed how a limited set of vulnerable sites could drive drug sensitivity."

The protective response depended on PARP1 activity and involved two other proteins: TIMELESS, which helps protect DNA replication, and DDX11, an enzyme capable of unwinding G4 structures. PARP inhibition disrupted this response in ESCO2-depleted cells. G4 structures accumulated further, DNA synthesis declined, and damage increased near centromeres. The resulting chromosome damage helped explain why these cells were particularly sensitive to the drugs.

The findings establish a mechanism connecting localized replication problems to cancer drug sensitivity. They also raise a broader possibility that treatments that produce more DNA damage may be lethal to cancer cells partly because they increase the chance of hitting particularly vulnerable genomic sites. Whether this principle extends to other genetic contexts and cancer treatments remains to be tested.

A member of Perlmutter Cancer Center, Dr. Rothenberg is working closely with clinicians to apply these approaches to patient-derived cancer cells and develop them for clinical use. The goal is to better understand how cancer drugs work and why patients respond—or fail to respond—to treatment. By identifying specific patterns of replication stress and DNA damage, the team aims to develop biomarkers that could help predict treatment response and guide more effective targeted therapies.

Dr. Rothenberg also directs NYU Langone's Single-Molecule Biophotonics Center, which provides other researchers with access to these methods and the expertise needed to apply them. The study was conducted in cancer cell models. Further preclinical and clinical research is needed to establish whether these features can guide treatment decisions in patients.

The study was a collaboration between NYU Langone and Pfizer. The work was supported in part by National Institutes of Health grants R01GM134947, R01AI153040, R01CA247773, R01GM139610, and R01ES031658. Dr. Gupta is supported by a postdoctoral fellowship from the Huntington Disease Society of America. Dr. Rothenberg's laboratory also receives support from Pfizer, Ionis Pharmaceuticals, and the Chang Chavkin Charitable Foundation. These relationships are being managed in keeping with NYU Langone policy.

Additional authors are Xia Ding, Lianglin Zhang, Kate E. Coleman, Grace Tang, Wei Ting C. Lee, Jon Oyer, Xiaolin Kang, Dana J. Ramms, Ziqi Yu, Todd VanArsdale, David Fenyo, and Tony T. Huang. The work involved researchers at NYU Grossman School of Medicine and Pfizer Oncology Research and Development. Ding is now at WuXi Biology, part of WuXi AppTec, and Lee is now at Regeneron Pharmaceuticals.

Zhang, Oyer, Kang, Ramms, Yu, and VanArsdale are Pfizer employees; Ding is a former Pfizer employee. The remaining authors declare no competing interests.

About NYU Langone Health 
NYU Langone Health is a fully integrated health system that consistently achieves the best patient outcomes through a rigorous focus on quality that has resulted in some of the lowest mortality rates in the nation. Vizient Inc. has ranked NYU Langone No. 1 out of 122 comprehensive academic medical centers across the nation five years in a row, and it continues to have the most No. 1– and top 10–ranked specialties among medical centers in the United States, according to U.S. News & World Report. NYU Langone offers a comprehensive range of medical services with one high standard of care across seven inpatient locations, its Perlmutter Cancer Center, and more than 400 outpatient locations in the New York City area and Florida. The system also includes two tuition-free medical schools, in Manhattan and on Long Island, and a vast research enterprise.

Media Contact:

Gregory.Williams@NYULangone.org

SOURCE NYU Langone Health System