Study Identifies How PARP Inhibitors Fight BRCA1, BRCA2 Tumor Cells

This drug class works by interfering with the ability of cancer cells to repair themselves after experiencing damage to their DNA, but how PARP inhibitors selectively kill cancer cells was previously unknown.

Researchers at Massachusetts General Hospital have found how poly (ADP-ribose) polymerase (PARP) inhibitors, an important class of anti-cancer drugs, could help improve treatment and prolong survival for patients with breast, prostate, and ovarian cancers, as well as other malignancies.

PARP inhibitors, such as olaparib (Lynparza), rucaparib (Rubraca), and niraparib (Zejula) are used to treat patients with cancers of the breast, ovaries, prostate, and pancreas, and are particularly effective against tumors carrying mutations in the BRCA1 and BRCA2 tumor suppressor genes, according to the study.

This drug class works by interfering with the ability of cancer cells to repair themselves after experiencing damage to their DNA, but how PARP inhibitors selectively kill cancer cells was previously unknown.

The researchers found that PARP inhibitors work by creating gaps in tumor-cell DNA that remain present through multiple cell cycles. Additionally, BRCA1/2 mutant cancer cells cannot respond to these gaps and therefore fail to repair properly, leading to the death of tumor cells, according to the study.

"These findings provide a mechanistic explanation of the selectivity of PARP inhibitors toward cancer cells, and they also offer new opportunities to improve the use of PARP inhibitors in the clinic," said Zou Lee, PhD, scientific co-director of the Mass General Cancer Center and the Center for Cancer Research, in a press release. "This work finally explains why PARP inhibitors kill BRCA-mutant cells selectively.”

The research has the potential to help clinical researchers better identify cells that are sensitive to PARP inhibitors and to find potential mechanisms by which cancer cells may develop resistance to PARP inhibitors, according to the study.

"We can actually monitor BRCA-mutant cells during PARP inhibitor therapy, and then watch them if they change during the therapy, and then we can predict when they will become resistant to the drugs," Lee said in the press release.

The research team hopes to develop a clinical test that helps decide whether BRCA-mutant cells are slowing in growth in the second cell cycle during PARP inhibitor treatment.

"We think that this slowdown is the reason for the development of resistance to PARP inhibitors. If the cells don't slow down, they should be sensitive to the drugs, but if they do slow down they may be developing resistance," Lee said in the press release.

REFERENCE

Researchers pinpoint how PARP inhibitors combat BRCA1 and BRCA2 tumor cells. ScienceDaily. August 12, 2021. Accessed September 7, 2021. https://www.sciencedaily.com/releases/2021/08/210812161905.htm