Let's Talk About Chemotherapy - PARP Inhibitors Discovery

Study Reveals New Mechanism of Action for Class of Targeted Therapy

Researchers have discovered a new way in which http://www.cancer.gov/dictionary?CdrID=660869 - 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 http://www.ncbi.nlm.nih.gov/pubmed/23118055 - study , led by Dr. Yves Pommier of the Laboratory of Molecular Pharmacology in NCI’s http://ccr.cancer.gov/ - Center for Cancer Research , was published November 1 in Cancer Research.

PARP inhibitors have shown http://www.cancer.gov/ncicancerbulletin/071310/page3#b - promising anticancer activity against breast and ovarian cancers in women with http://www.cancer.gov/dictionary?CdrID=46047 - BRCA1 or http://www.cancer.gov/dictionary?CdrID=46742 - BRCA2 gene mutations. The drugs were believed to block cancer cell growth by inhibiting the activity of http://www.cancer.gov/dictionary?CdrID=658048 - PARP http://www.cancer.gov/dictionary?CdrID=46092 - 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 http://www.cancer.gov/dictionary?CdrID=445093 - 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. http://www.cancer.gov/dictionary?CdrID=660871 - Olaparib (AZD2281) was the most potent PARP inhibitor followed by http://www.cancer.gov/dictionary?CdrID=660981 - veliparib (ABT-888) and then niraparib ( http://www.cancer.gov/drugdictionary?CdrID=615263 - MK-4827 ).

In contrast, cells treated with niraparib or olaparib formed the most potent PARP-DNA complexes. When combined with a DNA http://www.cancer.gov/dictionary?CdrID=45589 - 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 BRCA2function 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 http://www.cancer.gov/researchandfunding/intramural - .

http://www.cancer.gov/ncicancerbulletin/111312/page3#c - http://www.cancer.gov/ncicancerbulletin/111312/page3#c

http://www.medicalnewstoday.com/releases/252643.php - http://www.medicalnewstoday.com/releases/252643.php

PARP inhibitors are active in tumors with defects in DNA homologous recombination (HR) due to BRCA1/2 mutations. The phosphoinositide 3-kinase (PI3K) signaling pathway preserves HR steady state. We hypothesized that in BRCA-proficient triple-negative breast cancer (TNBC), PI3K inhibition would result in HR impairment and subsequent sensitization to PARP inhibitors. We show in TNBC cells that PI3K inhibition leads to DNA damage, downregulation of BRCA1/2, gain in poly-ADP-ribosylation, and subsequent sensitization to PARP inhibition. In TNBC patient–derived primary tumor xenografts, dual PI3K and PARP inhibition with BKM120 and olaparib reduced the growth of tumors displaying BRCA1/2 downregulation following PI3K inhibition. PI3K-mediated BRCA downregulation was accompanied by extracellular signal–regulated kinase (ERK) phosphorylation. Overexpression of an active form of MEK1 resulted in ERK activation and downregulation of BRCA1, whereas the MEK inhibitor AZD6244 increased BRCA1/2 expression and reversed the effects of MEK1. We subsequently identified that the ETS1 transcription factor was involved in the ERK-dependent BRCA1/2 downregulation and that knockdown of ETS1 led to increased BRCA1/2 expression, limiting the sensitivity to combined BKM120 and olaparib in 3-dimensional culture.

Significance: Treatment options are limited for patients with TNBCs. PARP inhibitors have clinical activity restricted to a small subgroup of patients with BRCA mutations. Here, we show that PI3K blockade results in HR impairment and sensitization to PARP inhibition in TNBCs without BRCA mutations, providing a rationale to combine PI3K and PARP inhibitors in this indication. Our findings could greatly expand the number of patients with breast cancer that would benefit from therapy with PARP inhibitors. On the basis of our findings, a clinical trial with BKM120 and olaparib is being initiated in patients with TNBCs. Cancer Discov; 2(11); 1036–47. ©2012 AACR.

Study Reveals New Mechanism of Action for Class of Targeted Therapy

PI3K Inhibition Impairs BRCA1/2 Expression and Sensitizes BRCA-Proficient Triple-Negative Breast Cancer to PARP Inhibition