Self-assembled nucleolipid G-quadruplexes act as multitarget decoys for oncogene suppression in pancreatic cancer
Abstract
KRAS mutations drive multiple cancers and represent an important therapeutic target, together with other oncogenic regulators such as MYC , KIT , and BCL2 that are critically involved in pancreatic cancer. Here we describe a novel therapeutic strategy based on stable nucleolipid-modified G-quadruplex (NLG4) structures. Cell viability assays demonstrate that the selected NLG4s strongly inhibit pancreatic cancer cell proliferation, whereas the same non-lipidic G-quadruplex sequences display minimal activity under comparable conditions. Owing to their distinctive physicochemical properties, including stabilization of parallel G-quadruplex structures and self-assembly into micellar aggregates, NLG4s efficiently internalize into cells and interact in a decoy approach, with key G-quadruplex unfolding factors, such as Unwinding Protein 1 (UP1) responsible for the activation of oncogenes’ promoters in cancer cells. This interaction leads to a marked downregulation of KRAS, cMYC, cKIT, and BCL2 expression. Suppression of these oncogenes profoundly affects pancreatic cancer cell fate, as evidenced by reduced expression of proliferation (Ki67) and anti-apoptotic (BCL2) markers. In addition, NLG4s treatment decreases inflammatory signaling mediated by NF-κB and inhibits major pro-proliferative kinase pathways, including ERK, AKT, and phosphorylated AKT. The therapeutic relevance of this decoy strategy is further supported by the observed potentiation of gemcitabine antitumor activity. Overall, these findings highlight NLG4s as a promising anticancer approach that simultaneously targets multiple oncogenic pathways through G-quadruplex-based decoy mechanisms, with translational potential for future pancreatic cancer treatment.
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BibTeX
@article{kivunga2026selfassembled,
title = {{Self-assembled nucleolipid G-quadruplexes act as multitarget decoys for oncogene suppression in pancreatic cancer}},
author = {Faith Kivunga and Virginie Baylot and Tina Kauss and Brune Vialet and Jules Simonin Garcia and Patricia Korczak and Zahraa Othman and Gilmar Salgado and Philippe Barthélémy},
journal = {Scientific Reports},
year = {2026},
month = oct,
doi = {10.1038/s41598-026-72237-z},
url = {https://www.nature.com/articles/s41598-026-72237-z},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Self-assembled nucleolipid G-quadruplexes act as multitarget decoys for oncogene suppression in pancreatic cancer
AU - Faith Kivunga
AU - Virginie Baylot
AU - Tina Kauss
AU - Brune Vialet
AU - Jules Simonin Garcia
AU - Patricia Korczak
AU - Zahraa Othman
AU - Gilmar Salgado
AU - Philippe Barthélémy
PY - 2026
DA - 2026/10/07
JO - Scientific Reports
DO - 10.1038/s41598-026-72237-z
UR - https://www.nature.com/articles/s41598-026-72237-z
AB - KRAS mutations drive multiple cancers and represent an important therapeutic target, together with other oncogenic regulators such as MYC , KIT , and BCL2 that are critically involved in pancreatic cancer. Here we describe a novel therapeutic strategy based on stable nucleolipid-modified G-quadruplex (NLG4) structures. Cell viability assays demonstrate that the selected NLG4s strongly inhibit pancreatic cancer cell proliferation, whereas the same non-lipidic G-quadruplex sequences display minimal activity under comparable conditions. Owing to their distinctive physicochemical properties, including stabilization of parallel G-quadruplex structures and self-assembly into micellar aggregates, NLG4s efficiently internalize into cells and interact in a decoy approach, with key G-quadruplex unfolding factors, such as Unwinding Protein 1 (UP1) responsible for the activation of oncogenes’ promoters in cancer cells. This interaction leads to a marked downregulation of KRAS, cMYC, cKIT, and BCL2 expression. Suppression of these oncogenes profoundly affects pancreatic cancer cell fate, as evidenced by reduced expression of proliferation (Ki67) and anti-apoptotic (BCL2) markers. In addition, NLG4s treatment decreases inflammatory signaling mediated by NF-κB and inhibits major pro-proliferative kinase pathways, including ERK, AKT, and phosphorylated AKT. The therapeutic relevance of this decoy strategy is further supported by the observed potentiation of gemcitabine antitumor activity. Overall, these findings highlight NLG4s as a promising anticancer approach that simultaneously targets multiple oncogenic pathways through G-quadruplex-based decoy mechanisms, with translational potential for future pancreatic cancer treatment.
SN - 2045-2322
ER -