{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T16:16:31Z","timestamp":1791994591843,"version":"4.4.0"},"reference-count":179,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T00:00:00Z","timestamp":1634083200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010845","name":"Pancare Foundation","doi-asserted-by":"publisher","award":["P2223-004A"],"award-info":[{"award-number":["P2223-004A"]}],"id":[{"id":"10.13039\/100010845","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001232","name":"Royal Australasian College of Physicians","doi-asserted-by":"publisher","award":["807572"],"award-info":[{"award-number":["807572"]}],"id":[{"id":"10.13039\/501100001232","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The overall survival of pancreatic ductal adenocarcinoma (PDAC) remains poor and its incidence is rising. Targetable mutations in PDAC are rare, thus novel therapeutic approaches are needed. Protein arginine methyltransferase 5 (PRMT5) overexpression is associated with worse survival and inhibition of PRMT5 results in decreased cancer growth across multiple cancers, including PDAC. Emerging evidence also suggests that altered RNA processing is a driver in PDAC tumorigenesis and creates a partial dependency on this process. PRMT5 inhibition induces altered splicing and this vulnerability can be exploited as a novel therapeutic approach. Three possible biological pathways underpinning the action of PRMT5 inhibitors are discussed; c-Myc regulation appears central to its action in the PDAC setting. Whilst homozygous MTAP deletion and symmetrical dimethylation levels are associated with increased sensitivity to PRMT5 inhibition, neither measure robustly predicts its growth inhibitory response. The immunomodulatory effect of PRMT5 inhibitors on the tumour microenvironment will also be discussed, based on emerging evidence that PDAC stroma has a significant bearing on disease behaviour and response to therapy. Lastly, with the above caveats in mind, current knowledge gaps and the implications and rationales for PRMT5 inhibitor development in PDAC will be explored.<\/jats:p>","DOI":"10.3390\/cancers13205136","type":"journal-article","created":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T21:36:15Z","timestamp":1634160975000},"page":"5136","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["PRMT5: An Emerging Target for Pancreatic Adenocarcinoma"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8075-3608","authenticated-orcid":false,"given":"Michael K. C.","family":"Lee","sequence":"first","affiliation":[{"name":"Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne,  VIC 3000, Australia"},{"name":"The University of Melbourne Centre for Cancer Research, Parkville,  VIC 3010, Australia"},{"name":"Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville,  VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean M.","family":"Grimmond","sequence":"additional","affiliation":[{"name":"The University of Melbourne Centre for Cancer Research, Parkville,  VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grant A.","family":"McArthur","sequence":"additional","affiliation":[{"name":"Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne,  VIC 3000, Australia"},{"name":"Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville,  VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2798-4703","authenticated-orcid":false,"given":"Karen E.","family":"Sheppard","sequence":"additional","affiliation":[{"name":"Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne,  VIC 3000, Australia"},{"name":"Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville,  VIC 3010, Australia"},{"name":"Department of Biochemistry and Pharmacology, University of Melbourne, Parkville,  VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1016\/S2468-1253(19)30347-4","article-title":"The global, regional, and national burden of pancreatic cancer and its attributable risk factors in 195 countries and territories, 1990\u20132017: A systematic analysis for the Global Burden of Disease Study 2017","volume":"4","author":"Pourshams","year":"2019","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2020","DOI":"10.1056\/NEJMoa1910231","article-title":"Nivolumab plus Ipilimumab in Advanced Non\u2013Small-Cell Lung Cancer","volume":"381","author":"Hellmann","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1056\/NEJMoa1910836","article-title":"Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma","volume":"381","author":"Larkin","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2518","DOI":"10.1200\/JCO.19.00934","article-title":"Five-Year Overall Survival for Patients with Advanced Non\u2012Small-Cell Lung Cancer Treated with Pembrolizumab: Results from the Phase I KEYNOTE-001 Study","volume":"37","author":"Garon","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Reck, M., Rodr\u00edguez-Abreu, D., Robinson, A.G., Hui, R., Cs\u0151szi, T., F\u00fcl\u00f6p, A., Gottfried, M., Peled, N., Tafreshi, A., and Cuffe, S. (2021). Five-Year Outcomes with Pembrolizumab versus Chemotherapy for Metastatic Non\u2013Small-Cell Lung Cancer with PD-L1 Tumor Proportion Score \u2265 50%. J. Clin. Oncol., JCO-21.","DOI":"10.1200\/JCO.21.00174"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1016\/S1470-2045(19)30388-2","article-title":"Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): Post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study","volume":"20","author":"Robert","year":"2019","journal-title":"Lancet Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2516","DOI":"10.1245\/s10434-020-08235-w","article-title":"Conditional Survival after Resection for Pancreatic Cancer: A Population-Based Study and Prediction Model","volume":"27","author":"Latenstein","year":"2020","journal-title":"Ann. Surg. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1200\/JCO.2021.39.3_suppl.416","article-title":"The impact of multi-agent chemotherapy in metastatic pancreatic adenocarcinoma: A population-based study utilizing the SEER database","volume":"39","author":"Sugumar","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2395","DOI":"10.1056\/NEJMoa1809775","article-title":"FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer","volume":"379","author":"Conroy","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1056\/NEJMoa1304369","article-title":"Increased Survival in Pancreatic Cancer with nab-Paclitaxel plus Gemcitabine","volume":"369","author":"Ervin","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.ejca.2016.11.026","article-title":"Underestimation of pancreatic cancer in the national cancer registry\u2014Reconsidering the incidence and survival rates","volume":"72","author":"Fest","year":"2017","journal-title":"Eur. J. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5018","DOI":"10.1158\/1078-0432.CCR-18-0531","article-title":"Molecular Profiling of Patients with Pancreatic Cancer: Initial Results from the Know Your Tumor Initiative","volume":"24","author":"Pishvaian","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1016\/S1470-2045(20)30074-7","article-title":"Overall survival in patients with pancreatic cancer receiving matched therapies following molecular profiling: A retrospective analysis of the Know Your Tumor registry trial","volume":"21","author":"Pishvaian","year":"2020","journal-title":"Lancet Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4674","DOI":"10.1158\/1078-0432.CCR-19-0191","article-title":"NRG1 gene fusions are recurrent, clinically actionable gene rearrangements in KRAS wild-type pancreatic ductal adenocarcinoma","volume":"25","author":"Jones","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1056\/NEJMoa1714448","article-title":"Efficacy of Larotrectinib in TRKFusion\u2013Positive Cancers in Adults and Children","volume":"378","author":"Drilon","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/S1470-2045(19)30691-6","article-title":"Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: Integrated analysis of three phase 1\u20132 trials","volume":"21","author":"Doebele","year":"2020","journal-title":"Lancet Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"12084","DOI":"10.1200\/JCO.2018.36.15_suppl.12084","article-title":"Incidence of Neuregulin1 (NRG1) gene fusions across tumor types","volume":"36","author":"Liu","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e16664","DOI":"10.1200\/JCO.2020.38.15_suppl.e16664","article-title":"NTRK gene fusions in bilio-pancreatic cancers","volume":"38","author":"Demols","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"175883592097561","DOI":"10.1177\/1758835920975613","article-title":"A systematic review and meta-analysis of neurotrophic tyrosine receptor kinase gene fusion frequencies in solid tumors","volume":"12","author":"Forsythe","year":"2020","journal-title":"Adv. Med. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1158\/2159-8290.CD-18-0275","article-title":"Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine","volume":"8","author":"Aguirre","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1158\/1078-0432.CCR-17-2994","article-title":"Genomics-Driven Precision Medicine for Advanced Pancreatic Cancer: Early Results from the COMPASS Trial","volume":"24","author":"Aung","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/nature16965","article-title":"Genomic analyses identify molecular subtypes of pancreatic cancer","volume":"531","author":"Bailey","year":"2016","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1158\/1078-0432.CCR-19-1543","article-title":"Altered Gene Expression along the Glycolysis\u2013Cholesterol Synthesis Axis Is Associated with Outcome in Pancreatic Cancer","volume":"26","author":"Karasinska","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1038\/ng.3398","article-title":"Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma","volume":"47","author":"Moffitt","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1038\/nm.2344","article-title":"Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy","volume":"17","author":"Collisson","year":"2011","journal-title":"Nat. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/s41588-019-0566-9","article-title":"Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution","volume":"52","author":"Kim","year":"2020","journal-title":"Nat. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Espiau-Romera, P., Courtois, S., Parejo-Alonso, B., and Sancho, P. (2020). Molecular and Metabolic Subtypes Correspondence for Pancreatic Ductal Adenocarcinoma Classification. J. Clin. Med., 9.","DOI":"10.3390\/jcm9124128"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1053\/j.gastro.2018.08.033","article-title":"Stratification of Pancreatic Ductal Adenocarcinomas Based on Tumor and Microenvironment Features","volume":"155","author":"Puleo","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1158\/1078-0432.CCR-20-2831","article-title":"Subtype-Discordant Pancreatic Ductal Adenocarcinoma Tumors Show Intermediate Clinical and Molecular Characteristics","volume":"27","author":"Topham","year":"2021","journal-title":"Clin. Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"107625","DOI":"10.1016\/j.celrep.2020.107625","article-title":"HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer","volume":"31","author":"Brunton","year":"2020","journal-title":"Cell Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4620","DOI":"10.1158\/0008-5472.CAN-20-0672","article-title":"EZH2 Regulates Pancreatic Cancer Subtype Identity and Tumor Progression via Transcriptional Repression of GATA6","volume":"80","author":"Patil","year":"2020","journal-title":"Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1016\/j.cell.2014.06.049","article-title":"Multiplatform Analysis of 12 Cancer Types Reveals Molecular Classification within and across Tissues of Origin","volume":"158","author":"Hoadley","year":"2014","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.ccell.2020.05.010","article-title":"Altered RNA Splicing by Mutant p53 Activates Oncogenic RAS Signaling in Pancreatic Cancer","volume":"38","author":"Penson","year":"2020","journal-title":"Cancer Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1038\/nature14985","article-title":"The spliceosome is a therapeutic vulnerability in MYC-driven cancer","volume":"525","author":"Hsu","year":"2015","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.ccell.2019.07.003","article-title":"Therapeutic Targeting of RNA Splicing Catalysis through Inhibition of Protein Arginine Methylation","volume":"36","author":"Fong","year":"2019","journal-title":"Cancer Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1042\/BJ20120768","article-title":"Protein arginine methyltransferase 5 is essential for growth of lung cancer cells","volume":"446","author":"Gu","year":"2012","journal-title":"Biochem. J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"8728","DOI":"10.18632\/aging.103198","article-title":"High PRMT5 expression is associated with poor overall survival and tumor progression in bladder cancer","volume":"12","author":"Tan","year":"2020","journal-title":"Aging"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.canlet.2018.04.019","article-title":"Protein arginine methyltransferase 5 promotes lung cancer metastasis via the epigenetic regulation of miR-99 family\/FGFR3 signaling","volume":"427","author":"Jing","year":"2018","journal-title":"Cancer Lett."},{"key":"ref_39","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_40","doi-asserted-by":"crossref","first-page":"4437","DOI":"10.7150\/thno.42047","article-title":"PRMT5-dependent transcriptional repression of c-Myc target genes promotes gastric cancer progression","volume":"10","author":"Liu","year":"2020","journal-title":"Theranostics"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1002\/ijc.31909","article-title":"LKB1 regulates PRMT5 activity in breast cancer","volume":"144","author":"Lattouf","year":"2019","journal-title":"Int. J. Cancer"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"381","DOI":"10.3892\/ijo.2017.3833","article-title":"The protein arginine methyltransferase 5 promotes malignant phenotype of hepatocellular carcinoma cells and is associated with adverse patient outcomes after curative hepatectomy","volume":"50","author":"Shimizu","year":"2017","journal-title":"Int. J. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.gendis.2019.06.002","article-title":"PRMT5 in gene regulation and hematologic malignancies","volume":"6","author":"Zhu","year":"2019","journal-title":"Genes Dis."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1146\/annurev-cancerbio-030617-050407","article-title":"Aberrant RNA Splicing in Cancer","volume":"3","author":"Knorr","year":"2019","journal-title":"Annu. Rev. Cancer Biol."},{"key":"ref_45","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_46","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_47","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1615\/CritRevImmunol.2020034789","article-title":"PRMT5 and Tip60 modify FOXP3 function in tumor immunity","volume":"40","author":"Goel","year":"2020","journal-title":"Crit. Rev. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1038\/nbt.4239","article-title":"Intron retention is a source of neoepitopes in cancer","volume":"36","author":"Smart","year":"2018","journal-title":"Nat. Biotechnol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"eaaz5683","DOI":"10.1126\/scitranslmed.aaz5683","article-title":"PRMT5 control of cGAS\/STING and NLRC5 pathways defines melanoma response to antitumor immunity","volume":"12","author":"Kim","year":"2020","journal-title":"Sci. Transl. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1158\/1535-7163.MCT-19-0189","article-title":"Selective PRMT5 Inhibitors Suppress Human CD8+ T Cells by Upregulation of p53 and Impairment of the AKT Pathway Similar to the Tumor Metabolite MTA","volume":"19","author":"Strobl","year":"2020","journal-title":"Mol. Cancer Ther."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"524","DOI":"10.3389\/fimmu.2019.00524","article-title":"NF-\u03baB\/mTOR\/MYC Axis Drives PRMT5 Protein Induction After T Cell Activation via Transcriptional and Non-transcriptional Mechanisms","volume":"10","author":"Webb","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1038\/s41590-018-0222-z","article-title":"Arginine methylation controls the strength of \u03b3c-family cytokine signaling in T cell maintenance","volume":"19","author":"Inoue","year":"2018","journal-title":"Nat. Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"S1334","DOI":"10.1016\/j.annonc.2021.08.2137","article-title":"Unicancer PRODIGE 24\/CCTG PA6 trial: Updated results of a multicenter international randomized phase III trial of adjuvant mFOLFIRINOX (mFFX) versus gemcitabine (gem) in patients (pts) with resected pancreatic ductal adenocarcinomas (PDAC)","volume":"32","author":"Conroy","year":"2021","journal-title":"Ann. Oncol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1056\/NEJMoa1011923","article-title":"FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer","volume":"364","author":"Conroy","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"4004","DOI":"10.1002\/cam4.2973","article-title":"Burden of hereditary cancer susceptibility in unselected patients with pancreatic ductal adenocarcinoma referred for germline screening","volume":"9","author":"Cremin","year":"2020","journal-title":"Cancer Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"4382","DOI":"10.1002\/cncr.29664","article-title":"Identification of germline genetic mutations in patients with pancreatic cancer","volume":"121","author":"Kelsen","year":"2015","journal-title":"Cancer"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1093\/jnci\/djy024","article-title":"Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms","volume":"110","author":"Lowery","year":"2018","journal-title":"JNCI J. Natl. Cancer Inst."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1056\/NEJMoa1903387","article-title":"Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer","volume":"381","author":"Golan","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1200\/JCO.2021.39.3_suppl.378","article-title":"Overall survival from the phase 3 POLO trial: Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer","volume":"39","author":"Golan","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3547","DOI":"10.1200\/JCO.2020.38.15_suppl.3547","article-title":"The prevalence of KRASG12C mutations utilizing circulating tumor DNA (ctDNA) in 80,911 patients with cancer","volume":"38","author":"Thein","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"439","DOI":"10.6004\/jnccn.2021.0017","article-title":"Pancreatic Adenocarcinoma, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology","volume":"19","author":"Tempero","year":"2021","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"4641","DOI":"10.1200\/JCO.2020.38.15_suppl.4641","article-title":"Comprehensive analysis of KRAS variants in patients (pts) with pancreatic cancer (PDAC): Clinical\/molecular correlations and real-world outcomes across standard therapies","volume":"38","author":"Hendifar","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1056\/NEJMoa1917239","article-title":"KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors","volume":"383","author":"Hong","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"3217","DOI":"10.1200\/JCO.20.01364","article-title":"Metastatic Pancreatic Cancer: ASCO Guideline Update","volume":"38","author":"Sohal","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"v56","DOI":"10.1093\/annonc\/mdv295","article-title":"Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"26","author":"Ducreux","year":"2015","journal-title":"Ann. Oncol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1038\/s41580-019-0155-x","article-title":"The regulation, functions and clinical relevance of arginine methylation","volume":"20","author":"Guccione","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"5853","DOI":"10.1093\/emboj\/cdf585","article-title":"Assisted RNP assembly: SMN and PRMT5 complexes cooperate in the formation of spliceosomal UsnRNPs","volume":"21","author":"Meister","year":"2002","journal-title":"EMBO J."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1933","DOI":"10.1242\/jcs.02882","article-title":"Methylation regulates the intracellular protein-protein and protein-RNA interactions of FMRP","volume":"119","author":"Dolzhanskaya","year":"2006","journal-title":"J. Cell Sci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1038\/s41573-021-00159-8","article-title":"Protein arginine methylation: From enigmatic functions to therapeutic targeting","volume":"20","author":"Wu","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2917","DOI":"10.1007\/s00018-019-03145-x","article-title":"Protein arginine methyltransferases: Insights into the enzyme structure and mechanism at the atomic level","volume":"76","author":"Tewary","year":"2019","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/j.tibs.2011.09.001","article-title":"Versatility of PRMT5-induced methylation in growth control and development","volume":"36","author":"Karkhanis","year":"2011","journal-title":"Trends Biochem. Sci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"8419","DOI":"10.1038\/ncomms9419","article-title":"Interplay between arginine methylation and ubiquitylation regulates KLF4-mediated genome stability and carcinogenesis","volume":"6","author":"Hu","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1785","DOI":"10.1038\/emboj.2012.17","article-title":"Arginine methylation controls growth regulation by E2F-1","volume":"31","author":"Cho","year":"2012","journal-title":"EMBO J."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3498","DOI":"10.1016\/j.celrep.2017.11.096","article-title":"PRMT5 Is a Critical Regulator of Breast Cancer Stem Cell Function via Histone Methylation and FOXP1 Expression","volume":"21","author":"Chiang","year":"2017","journal-title":"Cell Rep."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"3961","DOI":"10.1172\/JCI85239","article-title":"Targeting methyltransferase PRMT5 eliminates leukemia stem cells in chronic myelogenous leukemia","volume":"126","author":"Jin","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1038\/ncb1413","article-title":"Blimp1 associates with Prmt5 and directs histone arginine methylation in mouse germ cells","volume":"8","author":"Ancelin","year":"2006","journal-title":"Nat. Cell Biol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1038\/nature03813","article-title":"Blimp1 is a critical determinant of the germ cell lineage in mice","volume":"436","author":"Ohinata","year":"2005","journal-title":"Nature"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"12695","DOI":"10.1074\/jbc.M110.103911","article-title":"Methylation of Ribosomal Protein S10 By Protein-Arginine Methyltransferase 5 Regul. Ribosome Biogenesis","volume":"285","author":"Ren","year":"2010","journal-title":"J.  Biol. Chem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1038\/cr.2010.56","article-title":"PRMT5 regulates Golgi apparatus structure through methylation of the golgin GM130","volume":"20","author":"Zhou","year":"2010","journal-title":"Cell Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1158\/0008-5472.CAN-15-1766","article-title":"Arginine Methylation of SREBP1a via PRMT5 Promotes De Novo Lipogenesis and Tumor Growth","volume":"76","author":"Liu","year":"2016","journal-title":"Cancer Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"9630","DOI":"10.1128\/MCB.24.21.9630-9645.2004","article-title":"Human SWI\/SNF-Associated PRMT5 Methylates Histone H3 Arginine 8 and Negatively Regulates Expression of ST7 and NM23 Tumor Suppressor Genes","volume":"24","author":"Pal","year":"2004","journal-title":"Mol. Cell. Biol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1038\/ncb1802","article-title":"Arginine methylation regulates the p53 response","volume":"10","author":"Jansson","year":"2008","journal-title":"Nat. Cell Biol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/onc.2016.199","article-title":"PRMT5\u2013PTEN molecular pathway regulates senescence and self-renewal of primary glioblastoma neurosphere cells","volume":"36","author":"Russell","year":"2017","journal-title":"Oncogene"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"9711","DOI":"10.1038\/s41598-018-28002-y","article-title":"Activation of the p53-MDM4 regulatory axis defines the anti-tumour response to PRMT5 inhibition through its role in regulating cellular splicing","volume":"8","author":"Gerhart","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s12964-019-0344-4","article-title":"PRMT5 enhances tumorigenicity and glycolysis in pancreatic cancer via the FBW7\/cMyc axis","volume":"17","author":"Qin","year":"2019","journal-title":"Cell Commun. Signal."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1038\/ncb2158","article-title":"Crosstalk between Arg 1175 methylation and Tyr 1173 phosphorylation negatively modulates EGFR-mediated ERK activation","volume":"13","author":"Hsu","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2898","DOI":"10.1038\/s41375-019-0489-6","article-title":"PRMT5 is upregulated by B-cell receptor signaling and forms a positive-feedback loop with PI3K\/AKT in lymphoma cells","volume":"33","author":"Zhu","year":"2019","journal-title":"Leukemia"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2019","DOI":"10.1074\/mcp.R800013-MCP200","article-title":"A Genecentric Human Protein Atlas for Expression Profiles Based on Antibodies","volume":"7","author":"Berglund","year":"2008","journal-title":"Mol. Cell. Proteom."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"26580","DOI":"10.1073\/pnas.1911273116","article-title":"Pancreatic cancer organoids recapitulate disease and allow personalized drug screening","volume":"116","author":"Driehuis","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"28068","DOI":"10.1073\/pnas.2009899117","article-title":"Targeted CRISPR screening identifies PRMT5 as synthetic lethality combinatorial target with gemcitabine in pancreatic cancer cells","volume":"117","author":"Wei","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"PO-007","DOI":"10.1158\/1538-7445.PANCA20-PO-007","article-title":"Abstract PO-007: PRMT5 inhibition sensitizes pancreatic cancer to gemcitabine in orthotopic and metastatic murine models","volume":"80","author":"Kane","year":"2020","journal-title":"J. Cancer Res."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Shifteh, D., Sapir, T., Pahmer, M., Haimowitz, A., Goel, S., and Maitra, R. (2020). Protein Arginine Methyltransferase 5 as a Therapeutic Target for KRAS Mutated Colorectal Cancer. Cancers, 12.","DOI":"10.3390\/cancers12082091"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.ccell.2019.05.014","article-title":"Anti-tumor Activity of the Type I PRMT Inhibitor, GSK3368715, Synergizes with PRMT5 Inhibition through MTAP Loss","volume":"36","author":"Fedoriw","year":"2019","journal-title":"Cancer Cell"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"2031","DOI":"10.1038\/onc.2015.270","article-title":"Modulation of PKM alternative splicing by PTBP1 promotes gemcitabine resistance in pancreatic cancer cells","volume":"35","author":"Calabretta","year":"2016","journal-title":"Oncogene"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2343","DOI":"10.1101\/gad.1973010","article-title":"Alternative pre-mRNA splicing regulation in cancer: Pathways and programs unhinged","volume":"24","author":"David","year":"2010","journal-title":"Genes Dev."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1038\/nm.4493","article-title":"H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers","volume":"24","author":"Seiler","year":"2018","journal-title":"Nat. Med."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"4485","DOI":"10.1038\/onc.2013.392","article-title":"Epithelial splicing regulatory protein 1 is a favorable prognostic factor in pancreatic cancer that attenuates pancreatic metastases","volume":"33","author":"Ueda","year":"2014","journal-title":"Oncogene"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1002\/ijc.28327","article-title":"Alternatively spliced tissue factor contributes to tumor spread and activation of coagulation in pancreatic ductal adenocarcinoma","volume":"134","author":"Unruh","year":"2014","journal-title":"Int. J. Cancer"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1016\/S1091-255X(02)00036-7","article-title":"Ligand activation of alternatively spliced fibroblast growth factor receptor-1 modulates pancreatic adenocarcinoma cell malignancy","volume":"6","author":"Vickers","year":"2002","journal-title":"J. Gastrointest. Surg."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"3249","DOI":"10.1038\/onc.2015.384","article-title":"A novel protein isoform of the RON tyrosine kinase receptor transforms human pancreatic duct epithelial cells","volume":"35","author":"Chakedis","year":"2016","journal-title":"Oncogene"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2135","DOI":"10.1053\/j.gastro.2010.08.022","article-title":"KLF4\u03b1 Up-regulation Promotes Cell Cycle Progression and Reduces Survival Time of Patients with Pancreatic Cancer","volume":"139","author":"Wei","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2413","DOI":"10.1038\/onc.2015.318","article-title":"Aberrant RNA splicing in cancer; expression changes and driver mutations of splicing factor genes","volume":"35","author":"Sveen","year":"2016","journal-title":"Oncogene"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1038\/nrd3823","article-title":"The spliceosome as a target of novel antitumour drugs","volume":"11","author":"Bonnal","year":"2012","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1038\/nrc.2016.51","article-title":"RNA splicing factors as oncoproteins and tumour suppressors","volume":"16","author":"Dvinge","year":"2016","journal-title":"Nat. Rev. Cancer"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"2231","DOI":"10.1038\/s41388-019-1138-2","article-title":"Understanding aberrant RNA splicing to facilitate cancer diagnosis and therapy","volume":"39","author":"Dong","year":"2020","journal-title":"Oncogene"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/nature14351","article-title":"MYC regulates the core pre-mRNA splicing machinery as an essential step in lymphomagenesis","volume":"523","author":"Koh","year":"2015","journal-title":"Nature"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"3819","DOI":"10.1158\/0008-5472.CAN-05-4065","article-title":"Targeting the RNA Splicing Machinery as a Novel Treatment Strategy for Pancreatic Carcinoma","volume":"66","author":"Hayes","year":"2006","journal-title":"Cancer Res."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1111\/jcmm.14894","article-title":"PRMT5 promotes epithelial-mesenchymal transition via EGFR-\u03b2-catenin axis in pancreatic cancer cells","volume":"24","author":"Ge","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"4468","DOI":"10.18632\/aging.202407","article-title":"PRMT5 regulates colorectal cancer cell growth and EMT via EGFR\/Akt\/GSK3\u03b2 signaling cascades","volume":"13","author":"Yan","year":"2021","journal-title":"Aging"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"v159","DOI":"10.1093\/annonc\/mdz244","article-title":"METEOR-1: A Phase I Study of GSK3326595, a First-In-Class Protein Arginine Methyltransferase 5 (PRMT5) Inhibitor, in Advanced Solid Tumors","volume":"30","author":"Siu","year":"2019","journal-title":"Ann. Oncol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"S470","DOI":"10.1016\/j.annonc.2020.08.651","article-title":"537MO First-in-human study of JNJ-64619178, a protein arginine methyltransferase 5 (PRMT5) inhibitor, in patients with advanced cancers","volume":"31","author":"Villar","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"199","DOI":"10.15698\/cst2020.08.228","article-title":"PRMT5 function and targeting in cancer","volume":"4","author":"Kim","year":"2020","journal-title":"Cell Stress"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"10101","DOI":"10.1073\/pnas.1706978114","article-title":"Epigenetic control via allosteric regulation of mammalian protein arginine methyltransferases","volume":"114","author":"Jain","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1016\/S0021-9258(17)49877-2","article-title":"Protein arginine methyltransferase 5 represses tumor suppressor miRNAs that down-regulate CYCLIN D1 and c-MYC expression in aggressive B-cell lymphoma","volume":"295","author":"Karkhanis","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1038\/s41467-018-04006-0","article-title":"The LINC01138 drives malignancies via activating arginine methyltransferase 5 in hepatocellular carcinoma","volume":"9","author":"Li","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1084\/jem.20100830","article-title":"FBXW7 influences murine intestinal homeostasis and cancer, targeting Notch, Jun, and DEK for degradation","volume":"208","author":"Li","year":"2011","journal-title":"J. Exp. Med."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"9649","DOI":"10.1073\/pnas.0503677102","article-title":"Ras activity regulates cyclin E degradation by the Fbw7 pathway","volume":"102","author":"Minella","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1903","DOI":"10.1101\/gad.219899.113","article-title":"Regulation of constitutive and alternative splicing by PRMT5 reveals a role for Mdm4 pre-mRNA in sensing defects in the spliceosomal machinery","volume":"27","author":"Bezzi","year":"2013","journal-title":"Genes Dev."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/nrc2290","article-title":"FBW7 ubiquitin ligase: A tumour suppressor at the crossroads of cell division, growth and differentiation","volume":"8","author":"Welcker","year":"2008","journal-title":"Nat. Rev. Cancer"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"3788","DOI":"10.1158\/0008-5472.CAN-08-2846","article-title":"p53-Altered FBXW7 Expression Determines Poor Prognosis in Gastric Cancer Cases","volume":"69","author":"Yokobori","year":"2009","journal-title":"Cancer Res."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1111\/jcmm.14036","article-title":"Targeting PRMT5\/Akt signalling axis prevents human lung cancer cell growth","volume":"23","author":"Zhang","year":"2019","journal-title":"J. Cell. Mol. Med."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1828","DOI":"10.1002\/ijc.24879","article-title":"Loss of FBXW7, a cell cycle regulating gene, in colorectal cancer: Clinical significance","volume":"126","author":"Iwatsuki","year":"2010","journal-title":"Int. J. Cancer"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"E346","DOI":"10.1111\/hepr.12314","article-title":"Loss of FBXW7 expression is associated with poor prognosis in intrahepatic cholangiocarcinoma","volume":"44","author":"Enkhbold","year":"2014","journal-title":"Hepatol. Res."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"7692","DOI":"10.1074\/jbc.RA119.007640","article-title":"Protein arginine methyltransferase 5 (PRMT5) promotes survival of lymphoma cells via activation of WNT\/beta-catenin and AKT\/GSK3beta proliferative signaling","volume":"294","author":"Chung","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"4535","DOI":"10.1038\/s41467-018-07644-6","article-title":"GSK3 suppression upregulates \u03b2-catenin and c-Myc to abrogate KRas-dependent tumors","volume":"9","author":"Kazi","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_126","doi-asserted-by":"crossref","unstructured":"Duda, P., Akula, S.M., Abrams, S.L., Steelman, L.S., Martelli, A.M., Cocco, L., Ratti, S., Candido, S., Libra, M., and Montalto, G. (2020). Targeting GSK3 and Associated Signaling Pathways Involved in Cancer. Cells, 9.","DOI":"10.3390\/cells9051110"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"13516","DOI":"10.1073\/pnas.1311784110","article-title":"PRMT5 dimethylates R30 of the p65 subunit to activate NF- B","volume":"110","author":"Wei","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1038\/ncomms1975","article-title":"Proteomic screen reveals Fbw7 as a modulator of the NF-\u03baB pathway","volume":"3","author":"Arabi","year":"2012","journal-title":"Nat. Commun."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1038\/bjc.2011.509","article-title":"Overexpression of microRNA-223 regulates the ubiquitin ligase FBXW7 in oesophageal squamous cell carcinoma","volume":"106","author":"Kurashige","year":"2012","journal-title":"Br. J. Cancer"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1111\/j.1349-7006.2010.01801.x","article-title":"Reduced expression of ubiquitin ligase FBXW7 mRNA is associated with poor prognosis in breast cancer patients","volume":"102","author":"Ibusuki","year":"2011","journal-title":"Cancer Sci."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1038\/srep01311","article-title":"Loss of the major Type I arginine methyltransferase PRMT1 causes substrate scavenging by other PRMTs","volume":"3","author":"Dhar","year":"2013","journal-title":"Sci. Rep."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"e07938","DOI":"10.7554\/eLife.07938","article-title":"Cross-talk between PRMT1-mediated methylation and ubiquitylation on RBM15 controls RNA splicing","volume":"4","author":"Zhang","year":"2015","journal-title":"eLife"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1038\/s41594-019-0313-z","article-title":"PRMT5 methylome profiling uncovers a direct link to splicing regulation in acute myeloid leukemia","volume":"26","author":"Radzisheuskaya","year":"2019","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"13893","DOI":"10.1007\/s13277-016-5217-5","article-title":"Tumor suppressor Fbxw7 antagonizes WNT signaling by targeting \u03b2-catenin for degradation in pancreatic cancer","volume":"37","author":"Jiang","year":"2016","journal-title":"Tumor Biol."},{"key":"ref_135","first-page":"ra58","article-title":"Protein Arginine Methyltransferase 5 Regulates ERK1\/2 Signal Transduction Amplitude and Cell Fate through CRAF","volume":"4","author":"Tenbaum","year":"2011","journal-title":"Sci. Signal."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1158\/1541-7786.MCR-20-0745","article-title":"Protein Arginine Methyltransferase 5 (PRMT5) and the ERK1\/2 & PI3K Pathways: A Case for PRMT5 Inhibition and Combination Therapies in Cancer","volume":"19","author":"Sapir","year":"2021","journal-title":"Mol. Cancer Res."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1038\/s41467-021-21204-5","article-title":"PRMT5 inhibition disrupts splicing and stemness in glioblastoma","volume":"12","author":"Sachamitr","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1101\/gad.12.5.679","article-title":"Arginine methylation facilitates the nuclear export of hnRNP proteins","volume":"12","author":"Shen","year":"1998","journal-title":"Genes Dev."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"511","DOI":"10.3389\/fonc.2019.00511","article-title":"Genome-Wide Profiling Reveals the Landscape of Prognostic Alternative Splicing Signatures in Pancreatic Ductal Adenocarcinoma","volume":"9","author":"Yang","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"773","DOI":"10.3389\/fonc.2019.00773","article-title":"Genome-Wide Profiling of Prognostic Alternative Splicing Pattern in Pancreatic Cancer","volume":"9","author":"Yu","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1016\/S1097-2765(03)00101-1","article-title":"Methylation of SPT5 Regulates Its Interaction with RNA Polymerase II and Transcriptional Elongation Properties","volume":"11","author":"Kwak","year":"2003","journal-title":"Mol. Cell"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"4326","DOI":"10.1073\/pnas.1522372113","article-title":"Asymmetric arginine dimethylation of RelA provides a repressive mark to modulate TNF\u03b1\/NF-\u03baB response","volume":"113","author":"Reintjes","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"eaaw4640","DOI":"10.1126\/sciadv.aaw4640","article-title":"Arginine methylation expands the regulatory mechanisms and extends the genomic landscape under E2F control","volume":"5","author":"Roworth","year":"2019","journal-title":"Sci. Adv."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.molcel.2013.08.039","article-title":"Arginine Methylation-Dependent Reader-Writer Interplay Governs Growth Control by E2F-1","volume":"52","author":"Zheng","year":"2013","journal-title":"Mol. Cell"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.ccell.2018.12.010","article-title":"Integration of Genomic and Transcriptional Features in Pancreatic Cancer Reveals Increased Cell Cycle Progression in Metastases","volume":"35","author":"Connor","year":"2019","journal-title":"Cancer Cell"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"40488","DOI":"10.1038\/srep40488","article-title":"Functional analysis reveals that RBM10 mutations contribute to lung adenocarcinoma pathogenesis by deregulating splicing","volume":"7","author":"Zhao","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/j.ccell.2017.08.018","article-title":"Coordinated Splicing of Regulatory Detained Introns within Oncogenic Transcripts Creates an Exploitable Vulnerability in Malignant Glioma","volume":"32","author":"Braun","year":"2017","journal-title":"Cancer Cell"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1038\/ng.621","article-title":"Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders","volume":"42","author":"Ernst","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1101\/gad.247361.114","article-title":"Detained introns are a novel, widespread class of post-transcriptionally spliced introns","volume":"29","author":"Boutz","year":"2015","journal-title":"Genes Dev."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/0165-4608(95)00157-3","article-title":"Codeletion of the genes for p16INK4, methylthioadenosine phosphorylase, interferon-\u03b11, interferon-\u03b21, and other 9p21 markers in human malignant cell lines","volume":"86","author":"Zhang","year":"1996","journal-title":"Cancer Genet. Cytogenet."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.ccell.2017.07.007","article-title":"Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma","volume":"32","author":"Raphael","year":"2017","journal-title":"Cancer Cell"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1016\/j.celrep.2016.03.043","article-title":"MTAP Deletions in Cancer Create Vulnerability to Targeting of the MAT2A\/PRMT5\/RIOK1 Axis","volume":"15","author":"Marjon","year":"2016","journal-title":"Cell Rep."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"5038","DOI":"10.1093\/nar\/gkz200","article-title":"PRMT1 loss sensitizes cells to PRMT5 inhibition","volume":"47","author":"Gao","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1038\/nchembio.1810","article-title":"A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models","volume":"11","author":"Kuplast","year":"2015","journal-title":"Nat. Chem. Biol."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1016\/j.ajpath.2010.11.059","article-title":"Down-Regulation of Methylthioadenosine Phosphorylase (MTAP) Induces Progression of Hepatocellular Carcinoma via Accumulation of 5\u2032-Deoxy-5\u2032-Methylthioadenosine (MTA)","volume":"178","author":"Kirovski","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_156","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_157","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1021\/acsmedchemlett.9b00074","article-title":"Discovery of Potent and Selective Covalent Protein Arginine Methyltransferase 5 (PRMT5) Inhibitors","volume":"10","author":"Lin","year":"2019","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1021\/acsmedchemlett.9b00525","article-title":"Allosteric Modulation of Protein Arginine Methyltransferase 5 (PRMT5)","volume":"11","author":"Palte","year":"2020","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_159","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_160","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.molcel.2008.12.013","article-title":"Protein Arginine Methylation in Mammals: Who, What, and Why","volume":"33","author":"Bedford","year":"2009","journal-title":"Mol. Cell"},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1136\/gutjnl-2012-302529","article-title":"Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer","volume":"62","author":"Jacobetz","year":"2013","journal-title":"Gut"},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1126\/science.aad5214","article-title":"MTAPdeletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells","volume":"351","author":"Kryukov","year":"2016","journal-title":"Science"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1038\/nm.4097","article-title":"Modulation of splicing catalysis for therapeutic targeting of leukemia with mutations in genes encoding spliceosomal proteins","volume":"22","author":"Lee","year":"2016","journal-title":"Nat. Med."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1016\/j.ccell.2016.08.006","article-title":"Physiologic Expression of Sf3b1 K700E Causes Impaired Erythropoiesis, Aberrant Splicing, and Sensitivity to Therapeutic Spliceosome Modulation","volume":"30","author":"Obeng","year":"2016","journal-title":"Cancer Cell"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.ccell.2019.01.010","article-title":"Targeting an RNA-Binding Protein Network in Acute Myeloid Leukemia","volume":"35","author":"Wang","year":"2019","journal-title":"Cancer Cell"},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"14060","DOI":"10.1038\/ncomms14060","article-title":"Mutant U2AF1-expressing cells are sensitive to pharmacological modulation of the spliceosome","volume":"8","author":"Shirai","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1016\/j.molcel.2017.12.029","article-title":"The Augmented R-Loop Is a Unifying Mechanism for Myelodysplastic Syndromes Induced by High-Risk Splicing Factor Mutations","volume":"69","author":"Chen","year":"2018","journal-title":"Mol. Cell"},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1016\/j.ccr.2014.04.021","article-title":"Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma","volume":"25","author":"Rhim","year":"2014","journal-title":"Cancer Cell"},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/j.ccr.2014.04.005","article-title":"Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Reduced Survival","volume":"25","author":"Carstens","year":"2014","journal-title":"Cancer Cell"},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1158\/2159-8290.CD-18-0710","article-title":"IL1-Induced JAK\/STAT Signaling Is Antagonized by TGF\u03b2 to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma","volume":"9","author":"Biffi","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_171","first-page":"638","article-title":"HALO 109-301: A randomized, double-blind, placebo-controlled, phase 3 study of pegvorhyaluronidase alfa (PEGPH20) + nab-paclitaxel\/gemcitabine (AG) in patients (pts) with previously untreated hyaluronan (HA)-high metastatic pancreatic ductal adenocarcinoma (mPDA)","volume":"38","author":"Tempero","year":"2020","journal-title":"Pancreat. Cancer"},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"2458","DOI":"10.1016\/j.celrep.2017.11.003","article-title":"Pancreatic Adenocarcinoma Therapeutic Targets Revealed by Tumor-Stroma Cross-Talk Analyses in Patient-Derived Xenografts","volume":"21","author":"Nicolle","year":"2017","journal-title":"Cell Rep."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1001\/jamaoncol.2019.1588","article-title":"Durvalumab With or Without Tremelimumab for Patients With Metastatic Pancreatic Ductal Adenocarcinoma","volume":"5","author":"Oh","year":"2019","journal-title":"JAMA Oncol."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"S1195","DOI":"10.1016\/j.annonc.2020.08.2300","article-title":"LBA65 The Canadian Cancer Trials Group PA.7 trial: Results of a randomized phase II study of gemcitabine (GEM) and nab-paclitaxel (Nab-P) vs GEM, nab-P, durvalumab (D) and tremelimumab (T) as first line therapy in metastatic pancreatic ductal adenocarcino","volume":"31","author":"Renouf","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1038\/s41591-020-0880-x","article-title":"BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: The COMBAT trial","volume":"26","author":"Bockorny","year":"2020","journal-title":"Nat. Med."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1172\/JCI131254","article-title":"Protein arginine methyltransferase 5 promotes cholesterol biosynthesis\u2013mediated Th17 responses and autoimmunity","volume":"130","author":"Webb","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/s41467-018-07884-6","article-title":"PRMT5 is essential for B cell development and germinal center dynamics","volume":"10","author":"Litzler","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1093\/nar\/gkz637","article-title":"Hallmarks of ribosomopathies","volume":"48","author":"Kampen","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1038\/s41568-020-00302-4","article-title":"Non-genetic mechanisms of therapeutic resistance in cancer","volume":"20","author":"Marine","year":"2020","journal-title":"Nat. Rev. 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