In ovarian cancer, the combination of a PARP inhibitor and an inhibitor of BRDA4, a small regulatory molecule, is effective even in the absence of the BRCA1 or BRCA2 genetic defect.
Ovarian cancer is the most dangerous gynecological tumor and treatment options are still limited. Mutations in the BRCA1 and BRCA2 genes are common and play an important role in the development of this type of cancer.
Cells expressing an abnormality in these genes have non-functioning BRCA proteins and therefore cannot properly repair the damage that regularly occurs to their DNA. As a result, they are more likely to develop other genetic changes that can lead to cancer.
Blockade of DNA repair pathways
PARP inhibitors block another DNA repair pathway, which together with 2 non-functioning repair systems leads to the death of cells that already have a BRCA defect.
But in cells that have a functioning BRCA system, PARP inhibitors do not work because the BRCA-like DNA repair system is more important than the PARP system.
On the other hand, in functional BRCA ovarian cancers, it had been shown that blocking other DNA repair systems, the WEE and TOPBP1 systems, could lead to the efficacy of PARP inhibitors.
Interest of the associated blocking of a MET protein
Researchers at the Wistar Institute have found that by blocking a small molecule, BRD4, which is an upstream regulator of cellular transcription, it is possible to block cell repair. This BRD4 protein belongs to the BET protein family and it is quite simple to block it with a small inhibitory molecule and make the cells sensitive to PARP inhibitors.
The combination of BRD4 inhibitor and PARP inhibitor thus results in the destruction of ovarian cancer cells, even when they do not have a BRCA abnormality. The researchers therefore welcome this discovery, published in Cell Report, which extends the indications for PARP inhibitors to non-BRCA mutated ovarian cancers: “We have identified an effective and innovative strategy for sensitizing patients with ovarian cancer to PARP inhibitors”.
Applicable to other gynecological tumors
In practice, inhibiting BRD4, which belongs to the BET protein family, allows cells whose DNA is damaged by a PARP inhibitor to divide without repairing the damage, resulting in cell death by a phenomenon called “Mitotic catastrophe”.
The team tested the combination of PARP and BET inhibitors, in vivo, in a mouse model of ovarian cancer with normal BRCA1 and BRCA2. Although neither of the two inhibitors alone had an effect on tumor growth, the combination of the two results in a significant reduction in tumor mass.
“The joint use of these inhibitors can thus be applied to a wide variety of malignant tumors, regardless of the mutational status of the BRCA genes,” rejoices Sergey Karakashev, co-author of the study. “Therefore, our work will have wide-ranging applications in the development of novel combination therapies against cancer.”
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