A new study led by scientists at NYU Langone Health sheds light on how the major cancer gene BRCA2 determines which cancer cells can be killed by a class of precision cancer drugs called PARP inhibitors.
Recently published in Nature , the work builds on the fact that, as human cells divide and grow, DNA damage occurs continuously and must be swiftly repaired to prevent cancer. BRCA2 is a key player in such a mechanism, homology-directed repair, but genetic changes, called mutations, occur and accumulate in cells, with some sabotaging the gene's DNA repair role to create cancer risk.
Cancer cells also require DNA repair as their reckless growth causes a quick, lethal build-up of errors unless countered. When mutations hinder BRCA2 function, cancer cells are known to rely on the poly ADP-ribose polymerase 1 (PARP1) pathway for back-up DNA repair, and to continue abnormal growth. PARP inhibitors were designed to stop this.
Now the new study reveals an unexpected role for BRCA2 in controlling the action of PARP1 at DNA damage sites, and explains why PARP inhibitors are effective in some patients but not in others. The effectiveness of PARP inhibitors in any cancer cell, the study authors found, depends on how well BRCA2 works there.
While the percentage of cancer cells with functioning BRCA2 is hard to estimate accurately, it matters. As a proxy measure, past studies have shown that 15–20% of ovarian, 6–8% of breast, 8–10% of prostate, and 8–10% of pancreatic cancer cases feature either inherited BCRA2 mutations or those that arise for the first time as cells multiply in tumors.
"This work is part of a larger effort across NYU Langone and Perlmutter Cancer Center to connect molecular discovery with clinical advances," said senior study author Eli Rothenberg, Ph.D., professor in the Department of Biochemistry & Molecular Pharmacology at NYU Grossman School of Medicine, and director of Single Molecule Biophotonics. "Through collaborations with clinical teams, we are set to translate insights about BRCA-related pathways into actionable diagnostics and new treatment strategies."
Molecular Shield
While many cancer patients see a temporary remission with PARP inhibitors, results vary greatly. To understand why, and to clarify the BRCA2-PARP1 interplay, the research team turned to proprietary imaging techniques developed at NYU Langone.
"This finding would not have been possible without the specialized imaging tools pioneered by the Single Molecule Biophotonics program here," said Dr. Rothenberg. "They gave us a molecular window into how BRCA2 protects DNA repair complexes from disruption in living human cells in real time, bringing us closer to developing truly individualized cancer therapies."
Single-molecule imaging revealed that BRCA2 functions as a molecular shield, physically preventing PARP1 from remaining stuck at DNA repair sites, the mechanism by which PARP inhibitors have their effect. Specifically, the researchers found that intact BRCA2 ensures that RAD51—a protein essential for accurate DNA repair—can access repair sites instead of PARP1, and carry out its function. This prevents the treatment-generated buildup of harmful DNA breaks in cancer cells that resist PARP inhibition.
By contrast, in cells with defective BRCA2, PARP1 is free to bind to, and persist at, sites of DNA damage. This blocks RAD51 access and halts proper repair, causing fatal damage to cancer cells—a mechanism that explains the greater vulnerability of BRCA2-deficient tumor cells to PARP inhibitors.
"Moving forward, our team is focused on how this mechanism can be used clinically," said first study author Sudipta Lahiri, Ph.D., the postdoctoral fellow at NYU Langone who led the experimental work. "The finding that variable BRCA2 activity dictates PARP inhibitor efficacy points to the need for patient-specific tumor profiling and may inform how clinicians select therapies. We are also looking at the structure of BRCA2 domains involved in its ability to shield repair complexes from PARP1 with the goal of designing therapies that overcome resistance."
Along with Drs. Rothenberg and Lahiri, study authors from the Department of Biochemistry and Molecular Pharmacology at NYU Grossman School of Medicine included Tony Huang, Ph.D., professor of Biochemistry and Molecular Pharmacology; George Hamilton, Ph.D.; and M.D./Ph.D. student Liana Goehring. From the Department of Therapeutic Radiology at Yale University School of Medicine, co-authors included Gemma Moore and co-senior author Ryan Jensen, Ph.D.
The study was supported by National Institutes of Health grants GM134947, AI153040, GM139610, and ES031658 and National Cancer Institute grants CA247773, CA288368, CA270788, and CA215990. Additional support was provided by the V Foundation, the Gray Foundation, the Laura Chang and Arnold Chavkin Charitable Donation, the Goldberg Family Foundation, and a Perlmutter Cancer Center support grant.
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 115 comprehensive academic medical centers across the nation for three years in a row, and U.S. News & World Report recently placed nine of its clinical specialties among the top five in the nation. 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 320 outpatient locations in the New York area and Florida. With $14.2 billion in revenue this year, the system also includes two tuition-free medical schools, in Manhattan and on Long Island, and a vast research enterprise.
