title: 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 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.
authors.affiliation: Cancer Research Institute, Seoul National University, Seoul, Republic of Korea.
authors.forename: Ahrum
authors.initials: A
authors.lastname: Min
authors.forename: Seock-Ah
authors.initials: SA
authors.lastname: Im
authors.forename: Young-Kwang
authors.initials: YK
authors.lastname: Yoon
authors.forename: Sang-Hyun
authors.initials: SH
authors.lastname: Song
authors.forename: Hyun-Jin
authors.initials: HJ
authors.lastname: Nam
authors.forename: Hyung-Seok
authors.initials: HS
authors.lastname: Hur
authors.forename: Hwang-Phill
authors.initials: HP
authors.lastname: Kim
authors.forename: Kyung-Hun
authors.initials: KH
authors.lastname: Lee
authors.forename: Sae-Won
authors.initials: SW
authors.lastname: Han
authors.forename: Do-Youn
authors.initials: DY
authors.lastname: Oh
authors.forename: Tae-You
authors.initials: TY
authors.lastname: Kim
authors.forename: Mark J
authors.initials: MJ
authors.lastname: O'Connor
authors.forename: Woo-Ho
authors.initials: WH
authors.lastname: Kim
authors.forename: Yung-Jue
authors.initials: YJ
authors.lastname: Bang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D010793:Phthalazines / Q000008:administration & dosage*; D010879:Piperazines / Q000008:administration & dosage*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D004268:DNA-Binding Proteins; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C448305:RAD51C protein, human; D011838:Radiation-Sensitizing Agents; C531550:olaparib