{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:14:33Z","timestamp":1785428073365,"version":"3.56.0"},"reference-count":31,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32170590"],"award-info":[{"award-number":["32170590"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["32170590"],"award-info":[{"award-number":["32170590"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Methylthioadenosine phosphorylase (MTAP) deficiency caused by homozygous deletion is prevalent in solid tumors and contributes to malignant progression, thereby rendering cancer cells vulnerable to dysfunction of protein arginine methyltransferase 5 (PRMT5). This study aimed to investigate whether Poly (ADP-ribose) polymerase (PARP) inhibitors could exploit this vulnerability through PRMT5 inactivation in MTAP-deficient tumors. Methods: PRMT5 activity was assessed in vitro and in vivo following PARP inhibitor treatment. The antitumor effects of PARP inhibitors alone or in combination with either the MTAP inhibitor MTDIA or the PRMT5 inhibitor EPZ015666 were evaluated in solid tumor models, including MTAP-deficient tumor models in vivo. Results: PARP inhibitors effectively inactivated PRMT5 in vitro and in vivo and exacerbated DNA double-strand breaks induced by PARP inhibition. Moreover, PARP inhibitors showed significant synergistic effects when combined with either MTDIA or EPZ015666 in solid tumor models. MTAP-deficient tumors exhibited increased vulnerability to olaparib in vivo, and combined treatment with olaparib plus MTDIA or EPZ015666 produced improved therapeutic outcomes compared with olaparib alone. Conclusions: These findings identify PARP inhibitors as a potential therapeutic strategy for MTAP-deficient tumors through targeted inactivation of PRMT5 and support further evaluation of PARP inhibitor-based combination therapies in this molecular context.<\/jats:p>","DOI":"10.3390\/cancers18091335","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T08:11:14Z","timestamp":1776931874000},"page":"1335","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Inactivation of PRMT5 by PARP Inhibitors Confers High Susceptibility in MTAP-Deficient Cancers"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5131-4446","authenticated-orcid":false,"given":"Qi","family":"Liu","sequence":"first","affiliation":[{"name":"Key University Laboratory of Metabolism and Health of Guangdong, Biochemistry Department, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuling","family":"Sheng","sequence":"additional","affiliation":[{"name":"Key University Laboratory of Metabolism and Health of Guangdong, Biochemistry Department, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Folan","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Joint Laboratory of Guangdong & Hong Kong Universities for Vascular Homeostasis and Diseases, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8558-9717","authenticated-orcid":false,"given":"Haoyuan","family":"Tan","sequence":"additional","affiliation":[{"name":"Key University Laboratory of Metabolism and Health of Guangdong, Biochemistry Department, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyun","family":"Chang","sequence":"additional","affiliation":[{"name":"Cancer Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua Medicine, Tsinghua University, Beijing 102218, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6473-5826","authenticated-orcid":false,"given":"Xiaopeng","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen 518055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Human Cell Biology and Genetics, Joint Laboratory of Guangdong & Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Shenzhen Key Laboratory of Gene Regulation and Systems Biology, Southern University of Science and Technology, Shenzhen 518055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changzheng","family":"Du","sequence":"additional","affiliation":[{"name":"Cancer Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua Medicine, Tsinghua University, Beijing 102218, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1126\/science.aad5214","article-title":"MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells","volume":"351","author":"Kryukov","year":"2016","journal-title":"Science"},{"key":"ref_2","first-page":"100966","article-title":"A systematic literature review of MTAP deletions in solid and hematologic Cancers","volume":"44","author":"Clouser","year":"2025","journal-title":"Cancer Treat. Res. Commun."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"107963","DOI":"10.1016\/j.lungcan.2024.107963","article-title":"MTAP as an emerging biomarker in thoracic malignancies","volume":"197","author":"Brune","year":"2024","journal-title":"Lung Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.ccell.2020.12.010","article-title":"MAT2A Inhibition Blocks the Growth of MTAP-Deleted Cancer Cells by Reducing PRMT5-Dependent mRNA Splicing and Inducing DNA Damage","volume":"39","author":"Kalev","year":"2021","journal-title":"Cancer Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2643","DOI":"10.1016\/j.celrep.2018.08.002","article-title":"PRMT5 Regulates DNA Repair by Controlling the Alternative Splicing of Histone-Modifying Enzymes","volume":"24","author":"Hamard","year":"2018","journal-title":"Cell Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2046","DOI":"10.1158\/1541-7786.MCR-21-0093","article-title":"Epigenetic Regulation of Fanconi Anemia Genes Implicates PRMT5 Blockage as a Strategy for Tumor Chemosensitization","volume":"19","author":"Du","year":"2021","journal-title":"Mol. Cancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/s13402-020-00577-7","article-title":"Protein arginine methyltransferase 5: A potential cancer therapeutic target","volume":"44","author":"Yuan","year":"2021","journal-title":"Cell. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1126\/science.aad5944","article-title":"Disordered methionine metabolism in MTAP\/CDKN2A-deleted cancers leads to dependence on PRMT5","volume":"351","author":"Mavrakis","year":"2016","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4002","DOI":"10.1111\/febs.14297","article-title":"Reversible mono-ADP-ribosylation of DNA breaks","volume":"284","author":"Munnur","year":"2017","journal-title":"FEBS J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1146\/annurev-med-082523-083843","article-title":"New Therapeutic Options for BRCA Mutant Patients","volume":"76","author":"Ghanem","year":"2025","journal-title":"Annu. Rev. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2041","DOI":"10.1007\/s00018-015-1847-9","article-title":"The PRMT5 arginine methyltransferase: Many roles in development, cancer and beyond","volume":"72","author":"Stopa","year":"2015","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e188120","DOI":"10.1172\/JCI188120","article-title":"Targeting MTAP increases PARP inhibitor susceptibility in triple-negative breast cancer through a feed-forward loop","volume":"135","author":"Zeng","year":"2025","journal-title":"J. Clin. Investig."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5565","DOI":"10.1111\/jcmm.15213","article-title":"PRMT5 silencing selectively affects MTAP-deleted mesothelioma: In vitro evidence of a novel promising approach","volume":"24","author":"Barbarino","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2413","DOI":"10.1093\/bioinformatics\/btx162","article-title":"SynergyFinder: A web application for analyzing drug combination dose-response matrix data","volume":"33","author":"Ianevski","year":"2017","journal-title":"Bioinformatics"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Sauter, C., Simonet, J., Guidez, F., Dumetier, B., Pernon, B., Callanan, M., Bastie, J.N., Aucagne, R., and Delva, L. (2022). Protein Arginine Methyltransferases as Therapeutic Targets in Hematological Malignancies. Cancers, 14.","DOI":"10.3390\/cancers14215443"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3199","DOI":"10.1016\/j.celrep.2019.08.031","article-title":"A PRMT5-RNF168-SMURF2 Axis Controls H2AX Proteostasis","volume":"28","author":"Du","year":"2019","journal-title":"Cell Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4965","DOI":"10.1093\/nar\/gkp516","article-title":"PRMT5 is required for cell-cycle progression and p53 tumor suppressor function","volume":"37","author":"Scoumanne","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1016\/j.molcel.2017.01.019","article-title":"PRMT5-Dependent Methylation of the TIP60 Coactivator RUVBL1 Is a Key Regulator of Homologous Recombination","volume":"65","author":"Clarke","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2233","DOI":"10.1158\/2767-9764.CRC-23-0070","article-title":"PRMT5 Inhibitors Regulate DNA Damage Repair Pathways in Cancer Cells and Improve Response to PARP Inhibition and Chemotherapies","volume":"3","author":"Carter","year":"2023","journal-title":"Cancer Res. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1007\/s42764-022-00095-w","article-title":"PRMT1 and PRMT5: On the road of homologous recombination and non-homologous end joining","volume":"4","author":"Yin","year":"2023","journal-title":"Genome Instab. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1158\/2159-8290.CD-24-0887","article-title":"AMG 193, a Clinical Stage MTA-Cooperative PRMT5 Inhibitor, Drives Antitumor Activity Preclinically and in Patients with MTAP-Deleted Cancers","volume":"15","author":"Belmontes","year":"2025","journal-title":"Cancer Discov."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2412","DOI":"10.1158\/2159-8290.CD-23-0669","article-title":"MRTX1719 Is an MTA-Cooperative PRMT5 Inhibitor That Exhibits Synthetic Lethality in Preclinical Models and Patients with MTAP-Deleted Cancer","volume":"13","author":"Engstrom","year":"2023","journal-title":"Cancer Discov."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1038\/s41571-021-00532-x","article-title":"Understanding and overcoming resistance to PARP inhibitors in cancer therapy","volume":"18","author":"Dias","year":"2021","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1053\/j.seminoncol.2023.08.001","article-title":"PARP1 roles in DNA repair and DNA replication: The basi(c)s of PARP inhibitor efficacy and resistance","volume":"51","author":"Kanev","year":"2024","journal-title":"Semin Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"17562848211014818","DOI":"10.1177\/17562848211014818","article-title":"The role of PARP inhibitors in BRCA mutated pancreatic cancer","volume":"14","author":"Chi","year":"2021","journal-title":"Ther. Adv. Gastroenterol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Inoue, T., Sekito, S., Kageyama, T., Sugino, Y., and Sasaki, T. (2023). Roles of the PARP Inhibitor in BRCA1 and BRCA2 Pathogenic Mutated Metastatic Prostate Cancer: Direct Functions and Modification of the Tumor Microenvironment. Cancers, 15.","DOI":"10.3390\/cancers15092662"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Ragupathi, A., Singh, M., Perez, A.M., and Zhang, D. (2023). Targeting the BRCA1\/2 deficient cancer with PARP inhibitors: Clinical outcomes and mechanistic insights. Front. Cell. Dev. Biol., 11.","DOI":"10.3389\/fcell.2023.1133472"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"O\u2019Brien, S., Butticello, M., Thompson, C., Wilson, B., Wyce, A., Mahajan, V., Kruger, R., Mohammad, H., and Fedoriw, A. (2023). Inhibiting PRMT5 induces DNA damage and increases anti-proliferative activity of Niraparib, a PARP inhibitor, in models of breast and ovarian cancer. BMC Cancer, 23.","DOI":"10.1186\/s12885-023-11260-z"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2154","DOI":"10.1056\/NEJMoa1611310","article-title":"Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer","volume":"375","author":"Mirza","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1016\/j.ygyno.2021.12.025","article-title":"Olaparib maintenance monotherapy in platinum-sensitive relapsed ovarian cancer patients without a germline BRCA1\/BRCA2 mutation: OPINION primary analysis","volume":"164","author":"Poveda","year":"2022","journal-title":"Gynecol. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/s41467-024-55316-5","article-title":"MAT2A inhibitor AG-270\/S095033 in patients with advanced malignancies: A phase I trial","volume":"16","author":"Gounder","year":"2025","journal-title":"Nat. Commun."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/9\/1335\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T04:11:27Z","timestamp":1778127087000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/9\/1335"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,22]]},"references-count":31,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["cancers18091335"],"URL":"https:\/\/doi.org\/10.3390\/cancers18091335","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,22]]}}}