How inherited cancer risks can be used for effective personalized therapy microbiologystudy

Mutations in BRCA2—a gene known to repair damaged DNA and suppress tumor formation—can predict an individual’s predisposition to develop breast cancer, ovarian, prostate, pancreatic, and other epithelial tumors.

A new study led by scientists at Yale School of Medicine and New York University (NYU) Grossman School of Medicine unveils a previously unknown protective mechanism employed by the gene—and how an existing class of drugs used to treat cancer might be improved.

The study is published in the journal Nature.

The BRCA2 gene is known to play a crucial role in repairing and stabilizing DNA during cell replication. Mutations in the gene, however, can impair the DNA repair process and increase the risk of tumor formation. Cells have another protein called PARP1 [poly(ADP-ribose) polymerase 1] that flags damage to the DNA and errors in DNA replication, recruiting repair molecules before searching the genome for more errors. Since 2014, a class of drugs known as PARP inhibitors has been shown to help many BRCA2-deficient cancer patients achieve remission of tumors, at least temporarily.

Yet scientists have struggled to understand how it is that PARP inhibitors kill cancer cells in these patients and why this treatment usually has limited effectiveness.

Using biochemical and advanced single-molecule analysis technology, the research team—led by Ryan Jensen, associate professor of therapeutic radiology and pathology at Yale, and Eli Rothenberg, a professor of biochemistry and molecular pharmacology at NYU—discovered a dynamic interplay between the BRCA2, RAD51 (a protein that helps repair damaged DNA), and PARP1 proteins involved in the DNA repair. The primary job of BRCA2 is to regulate RAD51, a key player in the accurate recombination of DNA during cell division.

The researchers found, to their surprise, that when PARP inhibitors inadvertently trap PARP1 proteins on DNA, the PARP1 proteins can destabilize repair complexes and hinder DNA repair processes initiated by RAD51.

Remarkably, Jensen said, the BRCA2 gene effectively shields these complexes, maintaining the integrity and function of DNA repair pathways.

“Cancer cells can somehow tolerate the loss of the BRCA2 pathway, but when the PARP1 protein is inhibited, they die,” he said.

It remains unknown why the beneficial effects of PARP inhibitor therapies tend to wear off, Jensen said. However, the tools developed in this study will provide increased understanding of the detailed molecular interactions in patients with BRCA2 mutations and hopefully offer new leads to extend the benefits of PARP inhibitor therapy.