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The development of PARP inhibitors in ovarian cancer: from bench tobedside

View Article: PubMed Central - PubMed

ABSTRACT

The nuclear enzyme poly (ADP-ribose) polymerase (PARP) represents an importantnovel target in the treatment of ovarian cancer. This article charts over 50years of research from the discovery of the first PARP enzyme in 1963, to theapproval and licensing in 2015 of the first PARP inhibitor, olaparib (Lynparza),in the treatment of BRCA-mutated ovarian cancer.

No MeSH data available.


Synthetic lethality of PARP inhibitors in BRCA-deficientcells.
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fig3: Synthetic lethality of PARP inhibitors in BRCA-deficientcells.

Mentions: ‘Synthetic lethality' is the concept by which cancer cellsare selectively sensitive to the inactivation of two genes or pathways wheninactivation of either gene or pathway alone is non-lethal (Kaelin, 2005). This proposed mechanism of synthetic lethality ofPARP inhibitors in BRCA-deficient cells is outlined in Figure 3. Poly (ADP-ribose) polymerase inhibition leadsto the accumulation of DNA SSBs that result in unrepaired stalled replicationforks and ultimately DSBs. These DNA DSBs are normally repaired by the HRRpathway (Hoeijmakers, 2001). In HRR-defectivecells, that is, those with BRCA1/2 mutations, these DSBs areleft unrepaired or are repaired in an error-prone way by alternativenon-homologous end-joining DNA repair; both outcomes can result in genomicinstability and ultimately cell death. Whereas, in cells with functional HRR,that is, those with heterozygous mutations or wild-type BRCA, DSBs willbe accurately and efficiently repaired, and inhibiting PARP will not result incell death. Clinical trials are now confirming these preclinical datademonstrating that, as a class, PARP inhibitors are active in BRCAmcancers.


The development of PARP inhibitors in ovarian cancer: from bench tobedside
Synthetic lethality of PARP inhibitors in BRCA-deficientcells.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4816267&req=5

fig3: Synthetic lethality of PARP inhibitors in BRCA-deficientcells.
Mentions: ‘Synthetic lethality' is the concept by which cancer cellsare selectively sensitive to the inactivation of two genes or pathways wheninactivation of either gene or pathway alone is non-lethal (Kaelin, 2005). This proposed mechanism of synthetic lethality ofPARP inhibitors in BRCA-deficient cells is outlined in Figure 3. Poly (ADP-ribose) polymerase inhibition leadsto the accumulation of DNA SSBs that result in unrepaired stalled replicationforks and ultimately DSBs. These DNA DSBs are normally repaired by the HRRpathway (Hoeijmakers, 2001). In HRR-defectivecells, that is, those with BRCA1/2 mutations, these DSBs areleft unrepaired or are repaired in an error-prone way by alternativenon-homologous end-joining DNA repair; both outcomes can result in genomicinstability and ultimately cell death. Whereas, in cells with functional HRR,that is, those with heterozygous mutations or wild-type BRCA, DSBs willbe accurately and efficiently repaired, and inhibiting PARP will not result incell death. Clinical trials are now confirming these preclinical datademonstrating that, as a class, PARP inhibitors are active in BRCAmcancers.

View Article: PubMed Central - PubMed

ABSTRACT

The nuclear enzyme poly (ADP-ribose) polymerase (PARP) represents an importantnovel target in the treatment of ovarian cancer. This article charts over 50years of research from the discovery of the first PARP enzyme in 1963, to theapproval and licensing in 2015 of the first PARP inhibitor, olaparib (Lynparza),in the treatment of BRCA-mutated ovarian cancer.

No MeSH data available.