
The findings help bring individualized cancer therapies that much closer to reality.
Credit: Evan Oto / Science Source
A study led by scientists at 秘密研究所 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.
, 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 this mechanism鈥攈omology-directed repair鈥攂ut genetic changes, called mutations, occur and accumulate in cells, with some sabotaging the gene鈥檚 DNA repair role to create cancer risk.
Cancer cells also require DNA repair as their reckless growth causes a quick, lethal buildup 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 backup DNA repair, and to continue abnormal growth. PARP inhibitors were designed to stop this.
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 only some patients. 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 to 20 percent of ovarian, 6 to 8 percent of breast, 8 to 10 percent of prostate, and 8 to 10 percent of pancreatic cancer cases feature either inherited BCRA2 mutations or those that arise for the first time as cells multiply in tumors.
鈥淭his work is part of a larger effort across 秘密研究所 Langone and Perlmutter Cancer Center to connect molecular discovery with clinical advances,鈥 said senior study author , professor in the at 秘密研究所 Grossman School of Medicine, and director of Single Molecule Biophotonics. 鈥淭hrough collaborations with clinical teams, we are set to translate insights about BRCA-related pathways into actionable diagnostics and new treatment strategies.鈥
Molecular Shield
While many cancer patients see a temporary remission with PARP inhibitors, results vary greatly. To understand why, and to clarify the BRCA2鈥揚ARP1 interplay, the research team turned to proprietary imaging techniques developed at 秘密研究所 Langone.
鈥淭his finding would not have been possible without the specialized imaging tools pioneered by the Single Molecule Biophotonics program here,鈥 said Dr. Rothenberg. 鈥淭hey 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.鈥
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鈥攁 protein essential for accurate DNA repair鈥攃an 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鈥攁 mechanism that explains the greater vulnerability of BRCA2-deficient tumor cells to PARP inhibitors.
鈥淢oving forward, our team is focused on how this mechanism can be used clinically,鈥 said first study author Sudipta Lahiri, PhD, a postdoctoral fellow at 秘密研究所 Langone who led the experimental work. 鈥淭he 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.鈥
Along with Dr. Rothenberg and Dr. Lahiri, study authors from the Department of Biochemistry and Molecular Pharmacology included , professor of biochemistry and molecular Pharmacology; George Hamilton, PhD; and MD/PhD student Liana Goehring. From the Department of Therapeutic Radiology at Yale School of Medicine, co-authors included Gemma Moore and co-senior author Ryan Jensen, PhD.
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 秘密研究所 Langone Health
秘密研究所 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 秘密研究所 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. 秘密研究所 Langone offers a comprehensive range of medical services with one high standard of care across 7 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.
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