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|Ref Type||Journal Article|
|Authors||Min A, Im SA, Yoon YK, Song SH, Nam HJ, Hur HS, Kim HP, Lee KH, Han SW, Oh DY, Kim TY, O'Connor MJ, Kim WH, Bang YJ|
|Title||RAD51C-deficient cancer cells are highly sensitive to the PARP inhibitor olaparib.|
|Journal||Molecular cancer therapeutics|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
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|RAD51C loss||stomach cancer||sensitive||Olaparib||Preclinical - Cell line xenograft||Actionable||In a preclinical study, RAD51C-deficient gastric cancer cells demonstrated increased sensitivity to Lynparza (olaparib) compared to cells over expressing RAD51C, and Lynparza (olaparib) treatment inhibited tumor growth in RAD51C-deficient gastric cancer cell line xenograft models (PMID: 23512992).||23512992|