Small Molecule Inhibitor Disrupts Cell Growth in BRCA-Deficient Cancer

While BRCA1 and BRCA2 mutations are targets for cancer drugs, researchers at the Lewis Katz School of Medicine (LKSOM) at Temple University in Philadelphia discovered a new mechanism that aids precision medicine in treating BRCA-deficient cancers.

Richard T. Pomerantz, PhD, Assistant Professor of Medical Genetics and Molecular Biochemistry in the Fels Institute for Cancer Research at LKSOM, and this team, discovered a small-molecule disruption of RAD52 rings, which can selectively kill BRCA-deficient cancer cells by blocking the activity of an alternative DNA repair pathway.

The new findings were published November 5, 2015, in the journal Chemistry & Biology.

"Every cell has redundant DNA repair pathways," Dr. Pomerantz said in a press release. "If the main DNA repair pathway, BRCA-mediated homologous recombination, becomes defective, cancer cells adapt and still proliferate."

Cancer cells that adapt in this way may be more challenging to treat.

To address this issue, the research team screened more than 18,000 compounds before finding 6-hydroxy-DL-dopa (6-OH-dopa), the only small molecule that consistently prevented RAD52 from binding to single-stranded DNA. Experiments in cells showed that 6-OH-dopa disrupts RAD52 ring structures. In BRCA-deficient cells, treatment with the molecule resulted in reduced cell growth and viability. On the flip side, BRCA-proficient cells were not strongly affected, demonstrating the potential for a new form of treatment for this aggressive cancer type.

Dr. Pomerantz cleverly likened the effect to knocking out two table legs of a four-legged table, effectively collapsing the table. "Normal cells are left on three legs, due to only RAD52 inhibition, so they survive,” he explained.

The researchers were able to demonstrate that 6-OH-dopa selectively inhibits the proliferation of BRCA-deficient cancer cells, including those obtained from leukemia patients. It appears that they were able to conclude that small-molecule disruption of RAD52 rings as a promising mechanism for precision medicine in BRCA-deficient cancers.