In a recent study published in the journal Genes & Development, a team of researchers from Massachusetts General Hospital revealed how the class of drugs known as poly[ADP-ribose] polymerase (PARP) inhibitors exert their pharmacologic effects. Their findings could help improve cancer treatments and prolong survival in patients with breast, prostate, ovarian, and pancreatic cancers, as well as other malignancies.

The recent findings offer the possibility of monitoring tumors for the development of resistance to PARP-inhibitor therapy and identifying drug combinations that could thwart drug resistance and enhance the efficacy of cancer therapies. PARP inhibitors, such as olaparib, rucaparib and niraparib, are used to treat patients with cancers of the breast, ovary, prostate, and pancreas, and they are especially effective against tumors carrying mutations in the breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) tumor-suppressor genes.

PARP inhibitors, like many other classes of anticancer drugs, are known to work by interfering with the ability of cancer cells to repair themselves after experiencing damage to their DNA, but exactly how PARP inhibitors selectively kill cancer cells is poorly understood, according to the researchers.

Researcher Zou Lee, PhD, et al, discovered that PARP inhibitors work by creating gaps in tumor-cell DNA that remain present through multiple cell cycles (in which cells repeat the processes of replication, growth, and division). The researchers also found that BRCA1/2 mutant cancer cells cannot respond to these gaps and therefore fail to repair properly, leading to the death of tumor cells.

Dr. Lee stated, "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. This work finally explains why PARP inhibitors kill BRCA-mutant cells selectively." Dr. Lee added, "The discovery has the potential to help clinical researchers better identify cells that are sensitive to PARP inhibitors, and to identify potential mechanisms by which cancer cells may develop resistance to PARP inhibitors. 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."

Accordingly, Dr. Lee and colleagues suggested development of a clinical test to ascertain whether BRCA-mutant cells are slowing in growth in the second cell cycle during PARP-inhibitor treatment.  Dr. Lee noted, "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."

The researchers wrote that because the capacity of BRCA-mutant cells to slow down and thus develop resistance to PARP inhibitors is dependent on a master checkpoint protein (kinase) known as ataxia-telangiectasia and Rad3-related protein (ATR), it should be possible to combine PARP inhibitors with another class of drugs in development that is designed to inhibit ATR, thereby averting resistance to PARP inhibitors.

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