Abstract
A PARP inhibitor is a rationally designed targeted therapy for cancers with impaired DNA repair abilities. RAD51C is a paralog of RAD51 that has an important role in the DNA damage response. We found that cell lines sensitive to a novel oral PARP inhibitor, olaparib, had low levels of RAD51C expression using microarray analysis, and we therefore hypothesized that low expression of RAD51C may hamper the DNA repair process, resulting in increased sensitivity to olaparib. Compared with the cells with normal RAD51C expression levels, RAD51C-deficient cancer cells were more sensitive to olaparib, and a higher proportion underwent cell death by inducing G2-M cell-cycle arrest and apoptosis. The restoration of RAD51C in a sensitive cell line caused attenuation of olaparib sensitivity. In contrast, silencing of RAD51C in a resistant cell line enhanced the sensitivity to olaparib, and the number of RAD51 foci decreased with ablated RAD51C expression. We also found the expression of RAD51C was downregulated in cancer cells due to epigenetic changes and RAD51C expression was low in some gastric cancer tissues. Furthermore, olaparib significantly suppressed RAD51C-deficient tumor growth in a xenograft model. In summary, RAD51C-deficient cancer cells are highly sensitive to olaparib and offer preclinical proof-of-principle that RAD51C deficiency may be considered a biomarker for predicting the antitumor effects of olaparib.
Highlights
The DNA repair system is critical for maintaining genomic integrity
We hypothesized that RAD51C deficiency may be linked with the synthetic lethality associated with olaparib; a lack of RAD51C expression could be a marker of olaparib sensitivity
There is preclinical and clinical evidence showing that olaparib (AZD2281; KU-0059436), a small-molecule inhibitor of PARP, has potential as a therapeutic agent to treat cancers with BRCA1 and BRCA2 mutations that have an homologous recombination deficiency [1,2,3,4,5, 25, 26]
Summary
The DNA repair system is critical for maintaining genomic integrity. Synthetic lethality is defined as the loss of cell viability when multiple genes lose their functions altogether, especially when compensatory genes are defective. The concept of synthetic lethality has been shown using the novel PARP inhibitor in patients with breast and ovarian cancer harboring mutations in the BRCA1 or BRCA2 genes [1, 2]. If DSBs cannot be repaired because of homologous recombination dysfunction, genomic instability or cell death can result [6]. PARP inhibitors may be effective against various human cancer cells with defective DNA repair genes. An example of that is CDK1 depletion increased PARP inhibitor sensitivity in cancer cells because the DSBs induced by PARP inhibition could not be repaired because of inactivation of homologous recombination– associated repair in CDK1-depleted cells [7]. Recent study suggests that nonhomologous end joining (NHEJ) plays an important role in the genomic instability and hypersensitivity to PARP inhibitors in homologous recombination–deficient cells [8]
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