RAD51C-Deficient Cancer Cells Are Highly Sensitive to the PARP Inhibitor Olaparib

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 G 2 -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. Mol Cancer Ther; 12(6); 865-77. Ó2013 AACR.

The synthetic lethal killing of RAD54B-deficient colorectal cancer cells by PARP1 inhibition is enhanced with SOD1 inhibition

“…Influenced heavily by the initial observations involving BRCA1/ 2, a number of studies focused on HRR (or DDR) genes as putative interactors. Indeed, many of the identified interactors encode functions within HRR (or DDR) including RAD54L [27] , NBS [27, 30] , RAD51 [27, 30] , RAD51C [27, 31] , RAD51D [27, 32] , MRE11A [33] , XRCC1 [34] , XRCC2 [27] , ATR [30] , ATM [30] , DSS1 [30] , FANCC [30] and CHEK2 [30], and were identified through a combination of high-throughput screens [27, 28] and direct tests [30–33]. Thus, through direct tests, we have expanded this list to include RAD54B .…”

PALB2: The hub of a network of tumor suppressors involved in DNA damage responses

“…For example, defects in DSB repair are typically associated with increased sensitivity to radiation. Additionally, because the DSB-initiated HR pathway can rescue defects in base excision repair, mutation of genes in this network are typically also associated with hypersensitivity to PARP inhibitors [57, 58, 93, 103, 148–150]. Further, DNA interstrand crosslinking agents, including platinum compounds and nitrogen mustards are a major class of chemotherapeutic agents utilized to treat cancer [49].…”

Rad51 supports triple negative breast cancer metastasis

“…Paradoxically, Rad51 is overexpressed in multiple tumor types, including breast cancer [3]. Overexpression of RAD51 is due to increased transcription, reduced methylation and/or stabilization of the protein but not due to amplification of the RAD51 gene [4, 5]. Overexpression of RAD51 has also been suggested as a driver of aberrant recombination, resulting in excess DNA damage in precancerous cells.…”