PXD073019-1

PXD073019 is an original dataset announced via ProteomeXchange.

Title	Targeting PADI1/3 Restores KRAS Inhibitor Sensitivity in PDAC and CRC
Description	The development of KRAS(ON) and KRAS(OFF) inhibitors enabled the selective targeting of KRAS-addicted tumors, offering new therapeutic options for malignancies refractory to conventional treatments, such as metastatic colorectal cancer (CRC), lung adenocarcinoma (LUAD), and pancreatic ductal adenocarcinoma (PDAC). However, intrinsic or acquired resistance significantly limited their clinical potential. In this study, we demonstrated that in CRC and PDAC patients harboring activating KRAS mutations the expression of peptidylarginine deiminases PADI1 and, most notably, PADI3 represented negative prognostic markers. KRAS-driven metabolic rewiring, hypoxia, and acidosis sustained PADI1 and PADI3 expression through activation of an upstream enhancer of PADI1 locus. KRAS inhibition resulted in loss of PADI1 and PADI3 expression, whereas cellular models resistant to enforced KRAS degradation maintained basal expression levels of PADI1 and 3. Pharmacological inhibition of PADIs using BB-Cl-amidine or two selective PADI3 inhibitors synergized with KRAS(ON) and KRAS(OFF) inhibitors in two- and three-dimensional CRC and PDAC models, as well as in a PDAC murine xenograft. Integrated transcriptomic, proteomic, and CRISPR/Cas9 loss‑of‑function analyses revealed that co‑treatment altered the citrullination of extracellular matrix proteins and apoptotic regulators, inducing a non‑lytic apoptotic program without Damage‑Associated Molecular Pattern (DAMP) release. Collectively, our findings uncovered a novel therapeutic strategy to overcome resistance to KRAS inhibitors by exploiting a class of compounds that remained largely underexplored in oncology. We identified a distinct citrullinome in PDAC cells that had acquired resistance to LC-2 and were subsequently treated with LC-2 alone or in combination with BB-Cl-amidine. The goal was to uncover protein modifications that conferred insensitivity to KRAS degradation. Our analysis revealed extensive citrullination affecting apoptotic regulators, as well as extracellular matrix (ECM) components. These findings suggest that adaptive citrullination programs play a critical role in sustaining survival and drug tolerance under KRAS-targeted therapy, and that their disruption may represent a novel strategy to overcome resistance.
HostingRepository	PRIDE
AnnounceDate	2026-08-27
AnnouncementXML	Submission_2026-08-27_08:58:10.770.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Eros Di Giorgio
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2026-01-13 12:59:52	ID requested
⏵ 1	2026-08-27 08:58:11	announced

Dataset with its publication pending

submitter keyword: PADI1

PADI3

KRAS

CRC

PDAC

Eros Di Giorgio
contact affiliation	Laboratory of Biochemistry, Department of Medicine, University of Udine, Piazzale M. Kolbe 4, 33100 Udine, Italy
contact email	eros.digiorgio@uniud.it
lab head
Eros Di Giorgio
contact affiliation	University of Udine
contact email	eros.digiorgio@uniud.it
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/08/PXD073019

PRIDE project URI

• PRIDE
  1. PXD073019
     1. Label: PRIDE project
     2. Name: Targeting PADI1/3 Restores KRAS Inhibitor Sensitivity in PDAC and CRC