PXD082487-1

PXD082487 is an original dataset announced via ProteomeXchange.

Title	Engineering Palmitoylated G-Quadruplex Aptamers to Target STAT3 and Overcome Therapeutic Resistance in Pancreatic Cancer
Description	Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies owing to extensive therapeutic resistance and limited treatment options. Increasing evidence indicates that activation of the IL-6–JAK–STAT3 pathway represents a major adaptive survival mechanism that promotes resistance to both chemotherapy and KRAS-targeted therapies. Here, we investigated the role of STAT3 in PDAC resistance and developed G-quadruplex (G4) aptamers as selective inhibitors of STAT3 signalling. Reporter assays and transcriptomic analyses demonstrated enhanced STAT3 activation in PDAC cells resistant to chemotherapy and KRAS inhibitors. Based on the anti-STAT3 G4 aptamer T40214, we engineered monomeric variants (TT-STAT and TT-STATB) and demonstrated, by pull-down assays and mass spectrometry, their specific binding to endogenous STAT3, with TT-STAT preferentially recognizing the transcriptionally active dimer. To improve biological stability and intracellular delivery, we developed a palmitoylated G4 aptamer incorporated into functionalized liposomes (apt-637). Apt-637 effectively inhibited STAT3 transcriptional activity, disrupted STAT3 dimerization, reduced STAT3 occupancy at the anti-apoptotic Bcl2l1 and Mcl1 loci, and induced apoptosis in PDAC cells. Importantly, apt-637 significantly enhanced the efficacy of FOLFIRINOX and the KRAS(ON) inhibitor RMC-9805 in murine PDAC cells and patient-derived organoids, resulting in a marked reduction in ATP levels and enhanced apoptotic responses. Collectively, these findings identify STAT3 as a central mediator of adaptive resistance in PDAC and establish a lipophilic anti-STAT3 G4 aptamer delivered by functionalized liposomes as a promising therapeutic strategy to overcome compensatory survival signalling and enhance the efficacy of chemotherapy and KRAS-targeted therapies.
HostingRepository	PRIDE
AnnounceDate	2026-08-27
AnnouncementXML	Submission_2026-08-27_08:49:33.286.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Eros Di Giorgio
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2026-08-13 10:07:45	ID requested
⏵ 1	2026-08-27 08:49:34	announced

10.1111/febs.70475;

Xodo S, Driul L, Tolotto V, Di Giorgio E, Xodo LE, salvage in small-for-gestational-age placenta. FEBS J, 293(15):4554-4577(2026) [pubmed]

submitter keyword: aptamer

STAT3

KRAS

G4

Eros Di Giorgio
contact affiliation	University of Udine, Dept. of Medicine, 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

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PRIDE project URI

• PRIDE
  1. PXD082487
     1. Label: PRIDE project
     2. Name: Engineering Palmitoylated G-Quadruplex Aptamers to Target STAT3 and Overcome Therapeutic Resistance in Pancreatic Cancer