The study sheds light on how a major cancer gene influences the success of PARP inhibitors

The study sheds light on how a major cancer gene influences the success of PARP inhibitors

A study led by scientists at NYU Langone HealthBRCA2determines which cancer cells can be killed by a class of precision cancer drugs called PARP inhibitors.

Recently published inNatureThe work builds on the fact that DNA damage from the separation and growth of human cells occurs continuously and must be repaired quickly to prevent cancer.BRCA2is a key player in this 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 because their reckless growth causes a rapid, deadly buildup of errors unless countered. When mutations hinderBRCA2Functions are known that cancer cells rely on the poly ADP-ribose polymerase 1 (PARP1) pathway for backup DNA repair and continued normal growth. PARP inhibitors were developed to stop this.

The new study shows an unexpected role forBRCA2In controlling the action of PARP1 at DNA damage sites and explains why PARP inhibitors are only effective in some patients. The effectiveness of PARP inhibitors in each cancer cell depends on how wellBRCA2works there.

While the percentage of cancer cells with functioningBRCA2It's hard to estimate exactly, it's important. As a proxy measure, previous studies have shown that 15 to 20 percent of ovaries, 6 to 8 percent of breasts, 8 to 10 percent of prostates, and 8 to 10 percent of pancreatic cancer cases have either inherited BCRA2 mutations or those that appear for the first time as cells in tumors.

This work is part of a larger effort at NYU Langone and Perlmutter Cancer Center to connect molecular discovery with clinical advances. By collaborating with clinical teams, we will translate insightsBRCA-Related pathways into actionable diagnostics and new treatment strategies. “

Eli Rothenberg, PhD, senior study author, professor in the Department of Biochemistry and Molecular Pharmacology at NYU Grossman School of Medicine and director of Single Molecule Biophotonics

Molecular shield

While many cancer patients see temporary remission with PARP inhibitors, results vary widely. To understand why and to clarify to clarify theBRCA2-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 developed here by the single molecule biophotonics program,” said Dr. Rothenberg. “They gave us a molecular window, likeBRCA2Protects DNA repair complexes from disruption in living human cells in real time, bringing us closer to developing truly personalized cancer therapies. “

Single-molecule imaging showed thisBRCA2Functions as a molecular shield, preventing PARP1 from getting stuck at DNA repair sites, the mechanism by which PARP inhibitors have their effects. In particular, the researchers found that intactBRCA2ensures that RAD51 – a protein essential for accurate DNA repair – can access repair sites instead of PARP1 and carry out its function. This prevents the generated treatment of harmful DNA breaks in cancer cells that resist PARP inhibition.

In contrast, in cells with defectsBRCA2PARP1 is free to bind and stop at sites of DNA damage. This blocks Rad51 access and halts proper repair, leading to fatal damage to cancer cells—a mechanism that explains the greater susceptibility of BRCA2-deficient tumor cells to PARP inhibitors.

“Going forward, our team is focused on how this mechanism can be applied clinically,” said first study author Sudipta Lahiri, PhD, a postdoctoral fellow at NYU Langone who led the experimental work. “The determination of these variablesBRCA2Activity dictates the effectiveness of PARP inhibitors suggests the need for patient-specific tumor profiling and may inform how clinicians select therapies. We also consider the structure ofBRCA2Domains involved in its ability to protect complex repair from PARP1 to design therapies that overcome resistance. “

Together with Dr. Rothenberg and Dr. Lahiri authors included Department of Biochemistry and Molecular Pharmacology authors Tony T. Huang, PhD, 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 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.

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