PXD073473-1

PXD073473 is an original dataset announced via ProteomeXchange.

Title	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.
HostingRepository	PRIDE
AnnounceDate	2026-07-28
AnnouncementXML	Submission_2026-07-28_02:29:09.636.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Christof Lenz
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	timsTOF Pro 2

Revision	Datetime	Status	ChangeLog Entry
0	2026-01-23 13:04:14	ID requested
⏵ 1	2026-07-28 02:29:10	announced

Dataset with its publication pending

submitter keyword: pancreatic cancer, PRMT5, splicing, RBM39

Christof Lenz
contact affiliation	Core Facility Proteomics, Department of Clinical Chemistry, University Medical Center Goettingen, Germany
contact email	christof.lenz@med.uni-goettingen.de
lab head
Christof Lenz
contact affiliation	Max Planck Institute for Biophysical Chemistry
contact email	christof.lenz@mpibpc.mpg.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD073473
     1. Label: PRIDE project
     2. Name: Compensatory Spliceosomal Reprogramming Underlies PRMT5 inhibitor Adaptation in Pancreatic Cancer Cells