{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T15:58:37Z","timestamp":1759334317750,"version":"build-2065373602"},"reference-count":60,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T00:00:00Z","timestamp":1759104000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation of Korea (NRF) grant","award":["RS-2023-00240248"],"award-info":[{"award-number":["RS-2023-00240248"]}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["IJMS"],"abstract":"<jats:p>PARP inhibitors exploit synthetic lethality in BRCA1\/2-mutated ovarian cancers but are limited by emerging therapeutic resistance. Therefore, novel biomarkers predicting PARP inhibitor response are urgently needed. In this study, we performed integrative analysis using drug sensitivity, patient survival, gene dependency, and expression data to identify biomarkers associated with PARP inhibitor response in ovarian cancer. Mutations in BRCA1, MLL2, NF1, and SMARCA4 were associated with increased sensitivity to PARP inhibitors, suggesting potential synthetic lethality with PARP1. In contrast, SMAD4 mutations were linked to PARP inhibitor resistance, and low SMAD4 expression was associated with poor overall survival in patients with ovarian cancer. Further gene dependency score (GDS)-based screening revealed 51 candidate genes potentially involved in SMAD4-mediated resistance. Functional enrichment revealed associations with stress response, tumor-associated signaling pathways, and additional processes. Subsequent correlation and survival analyses nominated ACACA, PRPF4B, and TUBD1 as potential therapeutic targets. Notably, low ACACA expression in patients with low SMAD4 expression was associated with improved survival, indicating its relevance in overcoming PARP inhibitor resistance. This study contributes to predicting clinical outcomes in ovarian cancer and developing personalized treatment strategies.<\/jats:p>","DOI":"10.3390\/ijms26199530","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T15:38:55Z","timestamp":1759246735000},"page":"9530","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of Anticancer Targets in Ovarian Cancer Using Genomic Drug Sensitivity Data"],"prefix":"10.3390","volume":"26","author":[{"given":"Yebin","family":"Son","sequence":"first","affiliation":[{"name":"Department of Biotechnology, Duksung Women\u2019s University, 33 Samyang-Ro 144-Gil, Dobong-gu, Seoul 01369, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jae Yong","family":"Ryu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Systems Engineering, Soongsil University, 369 Sangdo-ro, Dongjak-gu, Seoul 06978, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"9","DOI":"10.20892\/j.issn.2095-3941.2016.0084","article-title":"Epidemiology of ovarian cancer: A review","volume":"14","author":"Reid","year":"2017","journal-title":"Cancer Biol. Med."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Jones, P.M., and Drapkin, R. (2013). Modeling High-Grade Serous Carcinoma: How Converging Insights into Pathogenesis and Genetics are Driving Better Experimental Platforms. Front. Oncol., 3.","DOI":"10.3389\/fonc.2013.00217"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1634\/theoncologist.8-6-541","article-title":"Cancer survival and incidence from the Surveillance, Epidemiology, and End Results (SEER) program","volume":"8","author":"Reichman","year":"2003","journal-title":"Oncologist"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"5037","DOI":"10.1158\/1078-0432.CCR-18-0784","article-title":"Consensus on Molecular Subtypes of High-Grade Serous Ovarian Carcinoma","volume":"24","author":"Chen","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1093\/oncolo\/oyab053","article-title":"Homologous Recombination Deficiency: Concepts, Definitions, and Assays","volume":"27","author":"Stewart","year":"2022","journal-title":"Oncologist"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1093\/jnci\/djy085","article-title":"Biomarkers for Homologous Recombination Deficiency in Cancer","volume":"110","author":"Hoppe","year":"2018","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1007\/s11523-021-00796-4","article-title":"An Overview of PARP Inhibitors for the Treatment of Breast Cancer","volume":"16","author":"Cortesi","year":"2021","journal-title":"Target. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1038\/nature03443","article-title":"Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase","volume":"434","author":"Bryant","year":"2005","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1038\/nature03445","article-title":"Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy","volume":"434","author":"Farmer","year":"2005","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/s41573-019-0046-z","article-title":"Synthetic lethality as an engine for cancer drug target discovery","volume":"19","author":"Huang","year":"2020","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1126\/science.278.5340.1064","article-title":"Integrating genetic approaches into the discovery of anticancer drugs","volume":"278","author":"Hartwell","year":"1997","journal-title":"Science"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1038\/s41392-020-00358-6","article-title":"Development of synthetic lethality in cancer: Molecular and cellular classification","volume":"5","author":"Li","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1007\/s11912-023-01488-0","article-title":"PARP Inhibitors in Breast Cancer: A Short Communication","volume":"26","author":"Daly","year":"2024","journal-title":"Curr. Oncol. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s13045-021-01061-x","article-title":"Prostate cancer and PARP inhibitors: Progress and challenges","volume":"14","author":"Teyssonneau","year":"2021","journal-title":"J. Hematol. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2473","DOI":"10.1056\/NEJMoa1104390","article-title":"Incorporation of bevacizumab in the primary treatment of ovarian cancer","volume":"365","author":"Burger","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"17041","DOI":"10.1073\/pnas.1305170110","article-title":"Stabilization of mutant BRCA1 protein confers PARP inhibitor and platinum resistance","volume":"110","author":"Johnson","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Sahu, A.D., Lee, J.S., Wang, Z., Zhang, G., Iglesias-Bartolome, R., Tian, T., Wei, Z., Miao, B., Nair, N.U., and Ponomarova, O. (2019). Genome-wide prediction of synthetic rescue mediators of resistance to targeted and immunotherapy. Mol. Syst. Biol., 15.","DOI":"10.15252\/msb.20188323"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.medj.2023.12.009","article-title":"A systematic analysis of the landscape of synthetic lethality-driven precision oncology","volume":"5","author":"Schaffer","year":"2024","journal-title":"Med"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1038\/s41698-024-00714-7","article-title":"Development of a polygenic score predicting drug resistance and patient outcome in breast cancer","volume":"8","author":"Sahu","year":"2024","journal-title":"NPJ Precis. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2926","DOI":"10.1038\/s41467-022-30582-3","article-title":"Mutational signatures are markers of drug sensitivity of cancer cells","volume":"13","author":"Levatic","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1038\/nature11005","article-title":"Systematic identification of genomic markers of drug sensitivity in cancer cells","volume":"483","author":"Garnett","year":"2012","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3111","DOI":"10.1111\/cas.14565","article-title":"Synthetic lethality strategies: Beyond BRCA1\/2 mutations in pancreatic cancer","volume":"111","author":"Hu","year":"2020","journal-title":"Cancer Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1038\/s41467-023-35880-y","article-title":"CRISPR screens reveal genetic determinants of PARP inhibitor sensitivity and resistance in prostate cancer","volume":"14","author":"Tsujino","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"baac030","DOI":"10.1093\/database\/baac030","article-title":"SynLethDB 2.0: A web-based knowledge graph database on synthetic lethality for novel anticancer drug discovery","volume":"2022","author":"Wang","year":"2022","journal-title":"Database"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3358","DOI":"10.1158\/0008-5472.CAN-21-0688","article-title":"Recruitment of KMT2C\/MLL3 to DNA Damage Sites Mediates DNA Damage Responses and Regulates PARP Inhibitor Sensitivity in Cancer","volume":"81","author":"Chang","year":"2021","journal-title":"Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/s41420-025-02306-1","article-title":"PARP inhibition-associated heterochromatin confers increased DNA replication stress and vulnerability to ATR inhibition in SMARCA4-deficient cells","volume":"11","author":"Yano","year":"2025","journal-title":"Cell Death Discov."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2487","DOI":"10.1016\/j.cell.2021.03.030","article-title":"Synthetic lethality-mediated precision oncology via the tumor transcriptome","volume":"184","author":"Lee","year":"2021","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1186\/s13073-024-01376-7","article-title":"Evolutionary dependency of cancer mutations in gene pairs inferred by nonsynonymous-synonymous mutation ratios","volume":"16","author":"Han","year":"2024","journal-title":"Genome Med."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Arildsen, N.S., Jonsson, J.M., Bartuma, K., Ebbesson, A., Westbom-Fremer, S., Masback, A., Malander, S., Nilbert, M., and Hedenfalk, I.A. (2017). Involvement of Chromatin Remodeling Genes and the Rho GTPases RhoB and CDC42 in Ovarian Clear Cell Carcinoma. Front. Oncol., 7.","DOI":"10.3389\/fonc.2017.00109"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Krill-Burger, J.M., Dempster, J.M., Borah, A.A., Paolella, B.R., Root, D.E., Golub, T.R., Boehm, J.S., Hahn, W.C., McFarland, J.M., and Vazquez, F. (2023). Partial gene suppression improves identification of cancer vulnerabilities when CRISPR-Cas9 knockout is pan-lethal. Genome Biol., 24.","DOI":"10.1186\/s13059-023-03020-w"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.1038\/ng.3984","article-title":"Computational correction of copy number effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells","volume":"49","author":"Meyers","year":"2017","journal-title":"Nat. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1093\/bib\/bbr049","article-title":"Gene set enrichment analysis: Performance evaluation and usage guidelines","volume":"13","author":"Hung","year":"2012","journal-title":"Brief. Bioinform."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"W90","DOI":"10.1093\/nar\/gkw377","article-title":"Enrichr: A comprehensive gene set enrichment analysis web server 2016 update","volume":"44","author":"Kuleshov","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1038\/nrc1411","article-title":"Biologically active sphingolipids in cancer pathogenesis and treatment","volume":"4","author":"Ogretmen","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.ctrv.2003.07.007","article-title":"PI3K\/Akt signalling pathway and cancer","volume":"30","author":"Casado","year":"2004","journal-title":"Cancer Treat. Rev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1186\/s13045-020-00949-4","article-title":"The MAPK and AMPK signalings: Interplay and implication in targeted cancer therapy","volume":"13","author":"Yuan","year":"2020","journal-title":"J. Hematol. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1038\/s41568-019-0216-7","article-title":"The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism","volume":"20","author":"Hoxhaj","year":"2020","journal-title":"Nat. Rev. Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"789174","DOI":"10.1155\/2012\/789174","article-title":"Insulin resistance and cancer risk: An overview of the pathogenetic mechanisms","volume":"2012","author":"Arcidiacono","year":"2012","journal-title":"Exp. Diabetes Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.gde.2009.10.009","article-title":"HIF-1: Upstream and downstream of cancer metabolism","volume":"20","author":"Semenza","year":"2010","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/S0955-0674(00)00194-0","article-title":"HIF-1 and mechanisms of hypoxia sensing","volume":"13","author":"Semenza","year":"2001","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Chen, W., Wu, P., Yu, F., Luo, G., Qing, L., and Tang, J. (2022). HIF-1alpha Regulates Bone Homeostasis and Angiogenesis, Participating in the Occurrence of Bone Metabolic Diseases. Cells, 11.","DOI":"10.3390\/cells11223552"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2381","DOI":"10.1242\/jcs.107.9.2381","article-title":"Characterization of very acidic phagosomes in breast cancer cells and their association with invasion","volume":"107","author":"Montcourrier","year":"1994","journal-title":"J. Cell Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1186\/s12943-019-1029-8","article-title":"The role of necroptosis in cancer biology and therapy","volume":"18","author":"Gong","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.cell.2008.10.051","article-title":"FAM\/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling, controls Smad4 monoubiquitination","volume":"136","author":"Dupont","year":"2009","journal-title":"Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.4161\/cbt.21792","article-title":"Genetic disruption of USP9X sensitizes colorectal cancer cells to 5-fluorouracil","volume":"13","author":"Harris","year":"2012","journal-title":"Cancer Biol. Ther."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"11230","DOI":"10.1074\/jbc.RA118.002715","article-title":"The Hippo pathway effector proteins YAP and TAZ have both distinct and overlapping functions in the cell","volume":"293","author":"Plouffe","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"305","DOI":"10.4252\/wjsc.v6.i3.305","article-title":"Sox2, a key factor in the regulation of pluripotency and neural differentiation","volume":"6","author":"Zhang","year":"2014","journal-title":"World J. Stem Cells"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2802","DOI":"10.3892\/mmr.2017.6328","article-title":"Expression levels of resistant genes affect cervical cancer prognosis","volume":"15","author":"Yang","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"102091","DOI":"10.1016\/j.tranon.2024.102091","article-title":"Disulfidptosis-related gene expression reflects the prognosis of drug-resistant cancer patients and inhibition of MYH9 reverses sorafenib resistance","volume":"49","author":"Zhang","year":"2024","journal-title":"Transl. Oncol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"D955","DOI":"10.1093\/nar\/gks1111","article-title":"Genomics of Drug Sensitivity in Cancer (GDSC): A resource for therapeutic biomarker discovery in cancer cells","volume":"41","author":"Yang","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Kalliokoski, T., Kramer, C., Vulpetti, A., and Gedeck, P. (2013). Comparability of mixed IC(5)(0) data\u2014A statistical analysis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0061007"},{"key":"ref_53","first-page":"A68","article-title":"The Cancer Genome Atlas (TCGA): An immeasurable source of knowledge","volume":"19","author":"Tomczak","year":"2015","journal-title":"Contemp. Oncol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1136\/bmj.328.7447.1073","article-title":"The logrank test","volume":"328","author":"Bland","year":"2004","journal-title":"BMJ"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene ontology: Tool for the unification of biology. The Gene Ontology Consortium","volume":"25","author":"Ashburner","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto encyclopedia of genes and genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Chen, E.Y., Tan, C.M., Kou, Y., Duan, Q., Wang, Z., Meirelles, G.V., Clark, N.R., and Ma\u2019ayan, A. (2013). Enrichr: Interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinform., 14.","DOI":"10.1186\/1471-2105-14-128"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1038\/s41596-018-0103-9","article-title":"Pathway enrichment analysis and visualization of omics data using g:Profiler, GSEA, Cytoscape and EnrichmentMap","volume":"14","author":"Reimand","year":"2019","journal-title":"Nat. Protoc."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"D638","DOI":"10.1093\/nar\/gkac1000","article-title":"The STRING database in 2023: Protein-protein association networks and functional enrichment analyses for any sequenced genome of interest","volume":"51","author":"Szklarczyk","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"D561","DOI":"10.1093\/nar\/gkq973","article-title":"The STRING database in 2011: Functional interaction networks of proteins, globally integrated and scored","volume":"39","author":"Szklarczyk","year":"2011","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/19\/9530\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T15:51:17Z","timestamp":1759247477000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/19\/9530"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,29]]},"references-count":60,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["ijms26199530"],"URL":"https:\/\/doi.org\/10.3390\/ijms26199530","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2025,9,29]]}}}