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Lenz"],"technology_type":["Mass Spectrometry","Bottom-up proteomics","Data-independent acquisition"],"disease":["Pancreatic Cancer"],"software":[""],"submitter_keywords":["Prmt5","Rbm39","Splicing","Pancreatic cancer"],"full_dataset_link":["https://www.ebi.ac.uk/pride/archive/projects/PXD073473"],"sample_protocol":["Cells were seeded one day prior to treatment with either combination therapy (4 nM JNJ-64619178 + 200 nM Indisulam) or DMSO control. The cell pellet was obtained and frozen in liquid nitrogen and further stored at -80°C. The further steps were performed by the Proteomics facility of the Universal medical center Göttingen. Cell pellets were lysed in a buffer containing 1% sodium deoxycholate (SDC) in 100 mM (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) (HEPES) assisted by sonication (Bioruptor pico, Diagenode). Protein extracts were cleaned and desalted using a magnetic bead-based SP3 protocol 36. Following tryptic digestion off the SP3 beads, peptide sample were acidified using 1% aqueous formic acid, adjusted to 2% acetonitrile, spiked with a synthetic peptide standard used for retention time alignment (iRT Standard, Schlieren, Switzerland) and kept at  +4°C for further analysis.  Samples were analyzed on a nanoflow chromatography system (nanoRSLC, Thermo Fisher Scientific) hyphenated to a hybrid timed ion mobility-quadrupole-time of flight mass spectrometer (timsTOF Pro 2, Bruker). In brief, 400 ng equivalents of peptides were enriched on a reversed-phase C18 trapping column (0.3 cm × 300 µm, Thermo Fisher Scientific) and separated on a reversed-phase C18 column with an integrated CaptiveSpray Emitter (Aurora 25 cm × 75 µm, IonOpticks) using a 100 min linear gradient of 5-34 % acetonitrile/0.1% formic acid (v:v) at 200 nl min-1, and a column temperature of 50 °C. DIA analysis was performed in diaPASEF mode 37 using a 20x2 variable size window acquisition method from m/z 400 to 1,200 to include the 2+/3+/4+ population in the m/z–ion mobility plane. The collision energy was ramped linearly as a function of the mobility from 59 eV at 1/K0=1.6 Vs cm−2 to 20 eV at 1/K0=0.6 Vs cm−2. Three technical replicates per biological replicate were acquired."],"repository":["Pride"],"quantification_method":[""],"modification":[""],"data_protocol":["Protein identification was achieved using the Pulsar algorithm in Spectronaut Software version 19.1 (Biognosys) using default settings. All DIA data were searched against the UniProtKB Homo sapiens reference proteome (revision 09/2024) augmented with a set of 54 known common laboratory contaminants at default settings. For quantitation, up to the 6 most abundant fragment ion traces per peptide, and up to the 10 most abundant peptides per protein were integrated and summed up to provide protein area values. Mass and retention time calibration as well as the corresponding extraction tolerances were dynamically determined. Both identification and quantification results were trimmed to a False Discovery Rate of 1 % using a forward-and-reverse decoy database strategy 38,39.  Protein quantification values were logarithmically transformed and technical duplicates were averaged. All proteins were annotated by gene names. The combination treatment and control were statistically compared with limma package (v3.62.2) in R (v4.4.2). A pre-ranked gene Set Enrichment Analysis (GSEA) was conducted on the protein list sorted by t-statistics. GSEA software from the BROAD institute was used (v4.4.4)."],"omics_type":["Proteomics"],"labhead":["Christof Lenz"],"instrument_platform":[""],"submission_type":["PARTIAL"],"labhead_affiliation":["Core Facility Proteomics, Department of Clinical Chemistry, University Medical Center Goettingen, Germany"],"species":["Homo Sapiens (human)"],"publication":["Not available"],"submitter_mail":["christof.lenz@mpibpc.mpg.de"],"submitter_affiliation":["Max Planck Institute for Biophysical Chemistry"],"submitter_country":["Germany"],"additional_accession":[]},"is_claimable":false,"name":"Compensatory Spliceosomal Reprogramming Underlies PRMT5 inhibitor Adaptation in Pancreatic Cancer Cells","description":"Pancreatic ductal adenocarcinoma (PDAC) remains a formidable clinical challenge. Next-generation protein arginine methyltransferase 5 (PRMT5) inhibitors show promising clinical results in a subset of PDACs with co-deletion of the tumor suppressor CDKN2A with the methylthioadenosine phosphorylase (MTAP) gene. However, primary and secondary resistance mechanisms limit the efficacy of this synthetic lethality approach. Our study reveals that compensatory spliceosomal reprogramming drives adaptation to PRMT5 inhibition in PDAC. Through comprehensive molecular profiling, we demonstrate that PRMT5 inhibitors induce marked upregulation of RNA-binding proteins, particularly RNA-binding protein 39 (RBM39), across diverse preclinical cellular models. We exploit this vulnerability by combining PRMT5 inhibition with Indisulam-mediated RBM39 degradation yielding synergistic activity. The combination strategy significantly enhanced apoptotic cell death and suppressed tumor outgrowth in resistance assays compared to single-agent treatments. We conducted multi-omics analysis revealing concomitant suppression of DNA repair machinery and metabolic pathways. Collectively, our work defines spliceosomal rewiring as a mechanism to limit cellular PRMT5 efficacy and nominates RBM39 as a therapeutically exploitable vulnerability, establishing the mechanistic foundation for dual targeting of the splicing machinery.","dates":{"publication":"2026-07-28","submission":"2026-01-23"},"accession":"PXD073473","cross_references":{"TAXONOMY":["NEWT:6945","NEWT:184922","NEWT:3555","NEWT:2","NEWT:157546","NEWT:35554","NEWT:38942","NEWT:307972","NEWT:32046","NEWT:544496","NEWT:2042546","NEWT:45351","NEWT:43179","NEWT:4513","NEWT:5722","NEWT:376741","NEWT:55153","NCBITaxon:10407","NEWT:1736309","NEWT:309800","NEWT:1211601","NEWT:876138","NEWT:3654","NEWT:237561","NEWT:5833","NEWT:6928","NEWT:10036","NEWT:36745","NEWT:1351","NEWT:1438992","NEWT:2649997","NEWT:272563","NEWT:224326","NCBITaxon:79857","NEWT:1096976","NEWT:95648","NEWT:3885","NEWT:3888","NEWT:1589","NEWT:135622","NCBITaxon:4896","NEWT:6915","NEWT:3649","NEWT:101510","NEWT:3880","NEWT:272559","NEWT:3641","NEWT:383379","NEWT:466585","NEWT:10029","NEWT:913645","NEWT:1000589","NEWT:85963","NEWT:85962","NEWT:317447","NEWT:7955","NEWT:7959","NEWT:2261","NEWT:31156","NEWT:398580","NEWT:4565","NEWT:1264690","NEWT:515619","NEWT:192875","NEWT:34305","NEWT:59729","NCBITaxon:183674","NEWT:224308","NEWT:84645","NEWT:626528","NEWT:139927","NEWT:4558","NEWT:209285","NEWT:5888","NEWT:1283","NEWT:931281","NEWT:4550","NEWT:1000561","NEWT:197","NEWT:1390363","NEWT:288705","NCBITaxon:79824","NEWT:4787","NCBITaxon:4563","NEWT:5755","NEWT:44689","NEWT:3218","NEWT:5759","NEWT:1736231","NEWT:1270","NEWT:374990","NEWT:2242","NEWT:4784","NEWT:11320","NEWT:360106","NEWT:286","NEWT:391619","NEWT:287","NEWT:10117","NEWT:10239","NEWT:10116","NEWT:1280","NEWT:1735272","NEWT:83334","NEWT:83332","NEWT:44685","NEWT:317513","NEWT:1148","NEWT:580240","NEWT:294128","NEWT:11676","NEWT:55571","NEWT:100226","NEWT:4530","NEWT:4896","NEWT:75058","NEWT:13616","NEWT:1390","NEWT:1094343","NEWT:296543","NEWT:1773","NEWT:1895","NEWT:1182590","NEWT:3712","NEWT:105023","NEWT:935293","NEWT:64152","NEWT:4924","NEWT:749200","NEWT:375146","NEWT:990346","NEWT:145953","NEWT:257309","NEWT:100816","NEWT:263","NEWT:230741","NEWT:52283","NEWT:284812","NCBITaxon:1313","NEWT:43330","NEWT:1603293","NEWT:408169","NEWT:44544","NEWT:4911","NEWT:645463","NEWT:3702","NEWT:129249","NEWT:243277","NEWT:990119","NEWT:408172","NEWT:408170","NEWT:493760","NEWT:260710","NEWT:257313","NEWT:400772","NEWT:3708","NEWT:128161","NEWT:332648","NEWT:106592","NEWT:536231","NEWT:460519","NEWT:1187947","NEWT:1432138","NEWT:10312","NEWT:1424507","NCBITaxon:1773","NEWT:9598","NEWT:8030","NEWT:1639","NEWT:188229","NEWT:3818","NEWT:480","NEWT:4909","NEWT:67767","NEWT:432359","NEWT:46835","NEWT:1182263","NEWT:2711","NEWT:376686","NEWT:95486","NEWT:9103","NEWT:29159","NEWT:253","NEWT:10306","NCBITaxon:2759","NEWT:1233435","NEWT:93061","NEWT:8022","NEWT:145943","NCBITaxon:4932","NEWT:595536","NEWT:240906","NEWT:593117","NEWT:3635","NEWT:5811","NEWT:235443","NEWT:272623","NEWT:272624","NEWT:411483","NEWT:884019","NEWT:198215","NEWT:411490","NEWT:983964","NEWT:169963","NEWT:32644","NEWT:225117","NEWT:499175","NEWT:109779","NEWT:476272","NEWT:3747","NEWT:195051","NEWT:367830","NEWT:1255228","NEWT:178616","NEWT:410289","NEWT:373153","NEWT:352472","NEWT:357","NEWT:360094","NEWT:470","NEWT:1313","NEWT:411469","NEWT:84023","NEWT:559292","NEWT:39491","NCBITaxon:5811","NEWT:411464","NEWT:411460","NEWT:2014887","NEWT:2762","NEWT:1174673","NEWT:562","NEWT:411470","NEWT:33952","NEWT:2094720","NCBITaxon:2697049","NEWT:571256","NEWT:28038","NEWT:1663","NEWT:1423","NEWT:4932","NEWT:3603","NEWT:2759","NEWT:3847","NEWT:327159","NEWT:178876","NEWT:327160","NEWT:573","NEWT:9031","NEWT:7091","NEWT:108931","NEWT:241368","NEWT:42528","NEWT:190802","NEWT:9778","NEWT:150475","NEWT:303","NEWT:9417","NEWT:7111","NEWT:347515","NEWT:1216979","NEWT:5180","NEWT:256737","NEWT:9541","NEWT:115104","NEWT:1121114","NEWT:663","NEWT:1081927","NEWT:1238993","NEWT:67825","NEWT:185579","NEWT:941442","NEWT:220668","NEWT:13076","NEWT:1249668","NEWT:7108","NEWT:317","NEWT:7227","NEWT:7469","NEWT:885318","NEWT:9402","NEWT:415540","NEWT:550","NEWT:675060","NEWT:4081","NEWT:334542","NEWT:554","NEWT:98334","NEWT:426428","NEWT:7574","NEWT:1715256","NEWT:7215","NEWT:575412","NEWT:29204","NEWT:2172103","NEWT:507601","NEWT:643680","NCBITaxon:6157","NEWT:746360","NEWT:6239","NEWT:470150","NEWT:216257","NEWT:102169","NEWT:9986","NEWT:4054","NEWT:73239","NEWT:226186","NEWT:1268063","NEWT:8782","NEWT:1263854","NEWT:435590","NEWT:1902","NEWT:160488","NEWT:28104","NEWT:1908","NEWT:13164","NEWT:216129","NCBITaxon:2","NEWT:985076","NEWT:1215323","NEWT:52641","NEWT:7038","NEWT:6192","NEWT:28532","NCBITaxon:38727","NEWT:353152","NEWT:2829","NEWT:366581","NEWT:216599","NEWT:216595","NEWT:1194669","NEWT:51329","NEWT:243230","NEWT:8355","NEWT:9685","NEWT:7029","NEWT:1080772","NEWT:8479","NEWT:1283300","NEWT:6183","NEWT:6063","NEWT:630","NEWT:334747","NEWT:61235","NEWT:15368","NEWT:6289","NEWT:436486","NEWT:6287","NEWT:300641","NEWT:727","NEWT:9796","NEWT:725","NEWT:170187","NEWT:469008","NEWT:260707","NEWT:256318","NCBITaxon:6191","NEWT:1836","NEWT:185431","NEWT:29760","NEWT:260704","NEWT:703612","NEWT:260705","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