New Understanding of PARP Inhibitors Could Expand the Number of Patients to Treat

Poly (ADP ribose) polymerase (PARP) inhibitors could have broader effectiveness in breast, ovarian, and prostate cancers, according to a study that uncovered the molecular mechanism of these drugs.

The researchers at UT Southwestern also identified a potential biomarker that would indicate when PARP inhibitors can be most effective.

“These findings could increase the patient population benefiting from these drugs by 2-, 3-, or 4-fold. Up to 70% of breast cancer patients could now be good candidates,” W. Lee Kraus, PhD, director of the Green Center for Reproductive Biology Sciences at UT Southwestern, said in a statement. “We have found that PARP inhibitors can act by a mechanism that is different from those previously identified, which rely on BRCA-dependent DNA repair pathways.”

The findings, which were published in Molecular Cell, may explain why patients with breast cancer who don’t have the BRCA gene are still responsive to PARP inhibitors. These treatments are used to disable a DNA repair pathway that cancer cells use to multiple and survive. However, Kraus and his team discovered that PARP inhibitors are also attacking ribosomes, which make proteins. Cancer cells rely on ribosomes because they support cell division.

“If you can slow down or inhibit the production of ribosomes, then you can slow down the growth of the cancer cell,” Kraus said.

This finding means cancers do not need a mutated BRCA gene to be sensitive to PARP inhibitors, which opens up more patients to potentially be treated with PARP inhibitors. Kraus and team also identified the protein DDX21, which is required to produce ribosomes and may be a potential new biomarker to indicate which patients could benefit from PARP inhibitors.

They found that patients with high levels of DDX21 may be the most responsive to treatment with PARP inhibitors, which also blocks DDX21 function and inhibits the ribosome production that cancers are dependent upon to grow and multiply.

Kraus is helping to develop clinical trials to treat breast and ovarian cancers.

“We started by trying to identify new molecular mechanisms and pursued this line of inquiry. We didn't know where the study would lead,” he said. “We started as pure basic scientists, but as the study progressed the clinical relevance became more evident.”

Reference

Kim D-S, Camacho CV, Nagari A, Malladi VS, Challa S, Kraus WL. Activation of PARP-1 by snoRNAs controls ribosome biogenesis and cell growth via the RNA helicase DDX21 [published online July 24, 2019]. Molecular Cell. doi: 10.1016/j.molcel.2019.06.020.