A newfound role for the cancer gene BRCA2 suggests why only select patients have benefited from treatment with PARP1 inhibitors to date. The results of a study by investigators at NYU Langone Health were recently published in the journal Nature.
In brief, PARP inhibitors act by impairing RAD51-mediated DNA strand exchange. However, BRCA2 protects the protein RAD51 structure and can counteract the instability created by PARP inhibition by preventing PARP1 from binding to DNA. BRCA2 prevents the PARP1 retention at homologous recombination repair sites induced by PARP inhibition. In tumors with BRCA2 deficiency, there is greater PARP1 retention observed, and thus, these cells are more sensitive to PARP inhibition.
“This finding would not have been possible without the specialized imaging tools pioneered by the Single Molecule Biophotonics program here. 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,” said senior study author Eli Rothenberg, PhD, Professor in the Department of Biochemistry and Molecular Pharmacology at NYU Grossman School of Medicine and Director of Single Molecule Biophotonics. He noted this study was part of a larger effort at NYU Langone and the Perlmutter Cancer Center to collaborate between molecular pharmacology and clinical teams to translate molecular insights into clinical advances.
Lahiri et al used proprietary single-molecule localization microscopy, which was developed at NYU Langone, to analyze BRCA2 on a cellular level. “Moving forward, our team is focused on how this mechanism can be used clinically,” said lead study author Sudipta Lahiri, PhD, a postdoctoral research fellow in the Department of Biochemistry and Molecular Pharmacology at NYU Langone. “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.”
Disclosure: For full disclosures of the study authors, visit nature.com.
