The mechanism of action suggests they may be effective even for patients without BRCA mutations.
PARP (poly ADP ribose polymerase) inhibitors have demonstrated success in treating patients with breast and ovarian cancers that have mutations in the BRCA1 or BRCA2 genes – genes that are involved in the repair of damaged DNA. The conventional understanding was that PARP inhibitors only work on patients with these mutations because the inhibitors block the action of the PARP enzymes and prevent the DNA in their cancer cells from being repaired, leading to cell death.
PARP inhibitors have also been shown to work in some patients without BRCA mutations. Researchers at the Green Center for Reproductive Biology Sciences UT Southwestern Medical Center have been exploring the mechanism of action of PARP inhibitors in more detail and have uncovered a mechanism of action that explains why these drugs may be a useful treatment of many other cancer patients.
The scientists found that in addition to blocking DNA repair, PARP inhibitors attack the ribosomes in cancer cells that produce proteins involved in rapid tumor cell growth. Specifically, blocking the PARP-1 protein also prevents the protein DDX21, which is present in nucleoli within the tumor cell nucleus, from entering the nucleus and blocking the transcription of ribosomal RNA, leading to significantly reduced protein production. Cancer cells require large quantities of protein for their rapid growth.
The next step is for the researchers to investigate whether DDX21 can serve as a biomarker — clinical trials are being designed for this purpose.