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ALDH1A1 Contributes to PARP Inhibitor Resistance Via Enhancing

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ALDH1A1 Contributes to PARP Inhibitor Resistance Via Enhancing Published OnlineFirst September 18, 2019; DOI: 10.1158/1535-7163.MCT-19-0242 MOLECULAR CANCER THERAPEUTICS | CANCER BIOLOGY AND TRANSLATIONAL STUDIES ALDH1A1 Contributes to PARP Inhibitor Resistance via Enhancing DNA Repair in BRCA2À/À Ovarian Cancer Cells Lu Liu1,2,3, Shurui Cai2,3, Chunhua Han2,3, Ananya Banerjee2,3,4,DayongWu2,3, Tiantian Cui2,3, Guozhen Xie2,3, Junran Zhang2,3, Xiaoli Zhang5, Eric McLaughlin5, Ming Yin6, Floor J. Backes7, Arnab Chakravarti2,3, Yanfang Zheng1, and Qi-En Wang2,3 ABSTRACT ◥ Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are that promotes homologous recombination (HR) by using an approved to treat recurrent ovarian cancer with BRCA1 or BRCA2 intrachromosomal MMEJ reporter. Moreover, NCT-501, an mutations, and as maintenance therapy for recurrent platinum- ALDH1A1-selective inhibitor, can synergize with olaparib in killing sensitive ovarian cancer (BRCA wild-type or mutated) after EOC cells carrying BRCA2 mutation in both in vitro cell culture treatment with platinum. However, the acquired resistance against and the in vivo xenograft animal model. Given that MMEJ activity PARPi remains a clinical hurdle. Here, we demonstrated that PARP has been reported to be responsible for PARPi resistance in inhibitor (olaparib)–resistant epithelial ovarian cancer (EOC) cells HR-deficient cells, we conclude that ALDH1A1 contributes to the À À exhibited an elevated aldehyde dehydrogenase (ALDH) activity, resistance to PARP inhibitors via enhancing MMEJ in BRCA2 / mainly contributed by increased expression of ALDH1A1 due to ovarian cancer cells. Our findings provide a novel mechanism olaparib-induced expression of BRD4, a member of bromodomain underlying PARPi resistance in BRCA2-mutated EOC cells and and extraterminal (BET) family protein. We also revealed that suggest that inhibition of ALDH1A1 could be exploited for pre- ALDH1A1 enhanced microhomology-mediated end joining venting and overcoming PARPi resistance in EOC patients carrying (MMEJ) activity in EOC cells with inactivated BRCA2, a key protein BRCA2 mutation. Introduction term survival in women with EOC has not increased significantly in the last 25 years (4). Ovarian cancer is the most lethal malignancy of the female repro- Poly (ADP-ribose) polymerase (PARP) inhibitors are an exciting ductive tract with a 5-year survival rate of only 29% in distant stages, at and promising new class of anticancer drugs. PARP inhibitors (PARPi) which approximately 60% of cases are diagnosed (1). It is estimated induce stalled replication forks by trapping the inactive PARP protein that in 2019, about 22,530 new cases of ovarian cancer will be on DNA and/or inhibiting single-strand break repair (5, 6). The stalled diagnosed and 13,980 women will die of ovarian cancer in the United replication forks, if not rescued, can be converted to more deleterious States (1). Over 90% of ovarian cancers are epithelial in origin, and double-strand breaks (DSB). DSBs are mainly repaired by error-free epithelial ovarian cancer (EOC), especially the most aggressive subtype homologous recombination (HR), which is mediated by BRCA1 and high-grade serous ovarian cancer, accounts for the majority of ovarian BRCA2, as well as error-prone nonhomologous end joining (NHEJ). cancer deaths (2, 3). Despite the progress of cancer treatment, long- The alternative NHEJ (alt-NHET), also called microhomology- mediated end joining (MMEJ), also plays a role in repairing DSBs, particularly in HR-deficient cells (7, 8). PARPi has been shown to be synthetically lethal with defective HR repair (9, 10) because the DSBs 1 Oncology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, caused by PARP inhibition depends on HR to repair. In contrast, Guangdong, China. 2Department of Radiation Oncology, College of Medicine, 3 enhanced classic NHEJ (c-NHEJ) promotes the cytotoxicity of The Ohio State University, Columbus, Ohio. The Ohio State University Com- fi prehensive Cancer Center, Columbus, Ohio. 4School of Biotechnology, KIIT HR-de cient cells treated with PARPi (11). PARPi have been approved Deemed to Be University, Bhubaneswar, Odisha, India. 5Center for Biostatistics, by the FDA for recurrent ovarian cancer with BRCA1 or BRCA2 Department of Biomedical Informatics, College of Medicine, The Ohio State mutations, and as maintenance therapy after first-line therapy for University, Columbus, Ohio. 6Division of Medical Oncology, Department of BRCA-mutated ovarian cancer, and as maintenance for recurrent Internal Medicine, College of Medicine, The Ohio State University, Columbus, 7 platinum-sensitive ovarian cancer after treatment with platinum Ohio. Department of Obstetrics and Gynecology, College of Medicine, The Ohio regardless of BRCA mutation. Thus, the number of patients taking State University, Columbus, Ohio. PARPi is increasing rapidly. However, resistance has been observed, Note: Supplementary data for this article are available at Molecular Cancer and patients receiving PARPi eventually develop cancer progression. Therapeutics Online (http://mct.aacrjournals.org/). Given that the greatest benefit of PARPi is seen in patients with BRCA L. Liu and S. Cai contributed equally to this article. mutations (>3 years improvement in PFS) than those without BRCA Corresponding Authors: Qi-En Wang, The Ohio State University, Room 1014, mutations (3–15 months improvement in PFS; ref. 12), understanding BRT, 460 W. 12th Avenue, Columbus, OH 43210. Phone: 614-292-9021; Fax: 614- the mechanism underlying PARPi resistance in BRCA mutated EOCs 292-9102; E-mail: [email protected]; and Yanfang Zheng, Oncology is particularly important. Center, Zhujiang Hospital, Southern Medical University, 253 Gongye Road, Aldehyde dehydrogenase (ALDH) is a superfamily of 19 known Guangzhou, Guangdong 510282, China. Phone: 86-20-62782360; E-mail: [email protected] enzymes participated in the metabolism of endogenous and exogenous aldehydes (13). High ALDH activity is observed in cancer stem cells Mol Cancer Ther 2020;19:199–210 (CSC) of multiple cancer types and is often used to isolate and doi: 10.1158/1535-7163.MCT-19-0242 functionally characterize CSCs (14). In addition, the high ALDH Ó2019 American Association for Cancer Research. activity has also been correlated with chemotherapy resistance in AACRJournals.org | 199 Downloaded from mct.aacrjournals.org on September 29, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst September 18, 2019; DOI: 10.1158/1535-7163.MCT-19-0242 Liu et al. various cancers (15–18). ALDH1A1 is a major member in the ALDH Gene Co., Ltd). siRNA designed to target human ALDH1A1 or BRD4 superfamily contributing to the ALDH activity. ALDH1A1 is upre- (Supplementary Table S1) were purchased from Dharmacon Inc. gulated more than 100-fold in ovarian cancer cells selected for taxane siRNA (100 nmol/L) was transfected into cells by Lipofectamine resistance in vitro, and ALDH1A1 knockdown reversed this chemo- 2000 transfection reagent. therapy resistance (19). Chemotherapy can also increase ALDH1A1 expression in patients and patient-derived ovarian tumor xeno- Cell survival measurement grafts (20, 21). ALDH can mediate resistance to chemotherapy via Cells were seeded in 96-well plates at an initial density of 1 Â 103 to direct drug metabolism and by regulation of reactive oxygen species 2 Â 103, incubated for 24 hours, and treated with various doses of (ROS), preventing ROS-mediated apoptosis in the drug-tolerant sub- PARPi or the ALDH1A1 inhibitor for 7 days. Cells were then washed population (22). ALDH1A1-mediated platinum resistance also corre- with PBS, fixed with 3.7% formaldehyde for 30 minutes, and stained lates with altered DNA-repair networks in the A2780 ovarian cancer with 1.0% methylene blue for 60 minutes. The plate was rinsed in cell line (23). However, it is unknown whether ALDH activity affects running water and then left to dry. Solvent (100 mL; 10% acetic acid, the sensitivity of EOC cells to PARPi, and whether ALDH1A1 can be 50% methanol and 40% H2O) was added to each well to dissolve the proposed as a therapeutic target to enhance PARPi efficacy in EOC. cells. Optical density of the released color was read at 630 nm. The In this study, we demonstrated that PARPi can enhance the ALDH relative cell survival was calculated with the values of vehicle-treated activity in BRCA2-mutated EOC cells, mainly through Bromodomain- cells set as 100%. Combination index (CI) was calculated by Chou's containing protein 4 (BRD4)-mediated enhancement of ALDH1A1 median-effect method (27) using CompuSyn Software. CI < 0.9, CI ¼ À/À expression. ALDH1A1 reduces the sensitivity of BRCA2 EOC cells 0.9 to 1.1, and CI > 1.1 denote synergistic effect, additive effect, and to PARPi, probably by augmenting MMEJ-mediated DSB repair. antagonistic effect, respectively. Selectively targeting ALDH1A1 by its inhibitor NCT-501 significantly À À sensitized BRCA2 / EOC cells to PARPi and rescued the sensitivity of ALDH analysis and cell sorting À À PARPi-resistant BRCA2 / EOC cells to olaparib. The ALDEFLUOR Assay kit (STEMCELL Technology) was used to analyze ALDH activity in cells, and sort ALDH-dim (ALDHdim) and ALDH-bright (ALDHbr) cells by using flow cytometry. Briefly, cells Materials and Methods were incubated with ALDEFLUOR reagents at 37C for 45 minutes Cell lines and reagents according to the manufacture's instruction. For each sample, À À EOC cell lines PEO1 (BRCA2 / ) and PEO4 (BRCA2 wild-type; one portion of cells was treated with 50 mmol/L diethylaminobenzal- ref. 24) were
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