Study Reveals New Mechanism of Action for Class of Targeted Therapy ► NCI Cancer Bulletin for November 13, 2012 - National Cancer Institute

NCI Cancer Bulletin for November 13, 2012 - National Cancer Institute

Study Reveals New Mechanism of Action for Class of Targeted Therapy

Researchers have discovered a new way in which PARP inhibitors block cancer cell growth. The researchers also have found that three experimental PARP inhibitors, which were presumed to have similar activities, vary widely in their ability to kill cancer cells. The study, led by Dr. Yves Pommier of the Laboratory of Molecular Pharmacology in NCI’s Center for Cancer Research, was published November 1 in Cancer Research.

PARP inhibitors have shown promising anticancer activity against breast and ovarian cancers in women with BRCA1 or BRCA2 gene mutations. The drugs were believed to block cancer cell growth by inhibiting the activity of PARP proteins, which help repair damaged DNA. Therefore, drugs with similar levels of PARP inhibition should have comparable anticancer effects. However, studies have indicated that treating cells with a PARP inhibitor causes more toxicity than would be achieved simply by loss of PARP activity, suggesting that these drugs may have a second mechanism of action.

The researchers showed that PARP inhibitors can also trap PARP proteins at sites of DNA damage, forming PARP-DNA complexes that are toxic to cells. The strength of the trapped PARP-DNA complexes correlated with a drug’s ability to kill cancer cells and varied widely between the three tested PARP inhibitors, which are currently being studied in clinical trials.

“While PARP inhibitors had been assumed to be of equivalent potency based on the degree to which they elicit PARP inhibition, we now know that they are not equivalent with respect to their potency to trap PARP,” said Dr. Pommier in a news release.

The new study also showed that PARP inhibition and PARP trapping are not directly related. Olaparib (AZD2281) was the most potent PARP inhibitor followed by veliparib (ABT-888) and then niraparib (MK-4827).

In contrast, cells treated with niraparib or olaparib formed the most potent PARP-DNA complexes. When combined with a DNA alkylating agent, niraparib and olaparib also were much more toxic to cancer cells than veliparib.

“Our findings suggest that clinicians who use PARP inhibitors in clinical trials should carefully choose their drug, because we now suspect results may differ, depending upon the PARP inhibitor used,” said first author Dr. Junko Murai, in a news release.

The researchers also investigated the effects of these PARP inhibitors on 30 cell lines that had different DNA repair genes inactivated. The results confirmed that cells without BRCA1 or BRCA2 function are more sensitive than normal cells to PARP inhibition. The study also revealed other genes not previously implicated in sensitizing cells to PARP inhibitors. These results may help determine which tumors are most likely to be susceptible to PARP inhibition.
This work was supported by NCI's Intramural Research Program.