000305545 001__ 305545
000305545 005__ 20251102023513.0
000305545 0247_ $$2doi$$a10.1053/j.gastro.2025.08.018
000305545 0247_ $$2pmid$$apmid:41143762
000305545 0247_ $$2ISSN$$a0016-5085
000305545 0247_ $$2ISSN$$a1528-0012
000305545 0247_ $$2altmetric$$aaltmetric:183045254
000305545 037__ $$aDKFZ-2025-02219
000305545 041__ $$aEnglish
000305545 082__ $$a610
000305545 1001_ $$aKöse, Hazal$$b0
000305545 245__ $$aTargeting Mutual Dependence of Phosphatidylinositol-3-Kinase α/δ and Small Ubiquitin-Like Modifier Signaling in Pancreatic Cancer.
000305545 260__ $$aNew York, NY$$bElsevier$$c2025
000305545 3367_ $$2DRIVER$$aarticle
000305545 3367_ $$2DataCite$$aOutput Types/Journal article
000305545 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1761658447_3682428
000305545 3367_ $$2BibTeX$$aARTICLE
000305545 3367_ $$2ORCID$$aJOURNAL_ARTICLE
000305545 3367_ $$00$$2EndNote$$aJournal Article
000305545 500__ $$aepub
000305545 520__ $$aPancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal cancer, with a 5-year survival rate of <13%. Despite advances in diagnostics and treatments, the standard of care for PDAC remains inadequate, and most patients develop resistance to therapy. Targeted approaches, such as Kirsten rat sarcoma (KRAS) inhibition, have shown promise in preclinical models, although clinical application remains challenged by the rapid development of resistance. The phosphatidylinositol-3-kinase (PI3K) signaling pathway is critical for PDAC development and maintenance, yet pharmacologic targeting has failed to yield significant clinical benefits.To investigate the relationship between the PI3K and small ubiquitin-like modifier (SUMO) pathways in PDAC, we used a comprehensive approach that included unbiased genome-wide clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeats-associated protein 9 resistance screens, pharmacologic screens, transcriptomics, proteomics, and phosphoproteomics experiments. Genetic knockout models were applied to validate our findings. A novel molecularly targeted combination therapy was tested in preclinical mouse models.Using genetic and pharmacologic screenings, we discovered a mutual and targetable codependence between the PI3K and the SUMO pathways. Simultaneous inhibition of PIK3α and PIK3δ, combined with SUMO-activating E1 targeting, triggered synthetic lethality and cell death. In syngeneic orthotopic immune-competent PDAC models, this combination therapy reduced tumor growth and promoted immune cell infiltration and activity.Our study introduces a novel rational combination therapy in PDAC. Dual targeting of PI3Kα/δ and SUMO signaling bears potential for clinical translation.
000305545 536__ $$0G:(DE-HGF)POF4-899$$a899 - ohne Topic (POF4-899)$$cPOF4-899$$fPOF IV$$x0
000305545 588__ $$aDataset connected to CrossRef, PubMed, , Journals: inrepo02.dkfz.de
000305545 650_7 $$2Other$$aCombination Therapy
000305545 650_7 $$2Other$$aPI3K
000305545 650_7 $$2Other$$aPancreatic Cancer
000305545 650_7 $$2Other$$aRegulated Cell Death
000305545 650_7 $$2Other$$aSUMOylation
000305545 7001_ $$aSchneeweis, Christian$$b1
000305545 7001_ $$aPutze, Philipp$$b2
000305545 7001_ $$aContreras, Constanza Tapia$$b3
000305545 7001_ $$aFerreiro, Laura$$b4
000305545 7001_ $$aWitte, Leonie$$b5
000305545 7001_ $$aDeidda, Ilaria$$b6
000305545 7001_ $$aHerzberg, Frederik$$b7
000305545 7001_ $$aEbert, Sophie$$b8
000305545 7001_ $$0P:(DE-He78)99460bdc44722b972a7b75d603ee525a$$aJakubik, Juraj$$b9$$udkfz
000305545 7001_ $$0P:(DE-He78)acb61b933ca50ec93e1c11b78d3d9e62$$aMoldaner, Leoni$$b10$$udkfz
000305545 7001_ $$aTodorovic, Jovan$$b11
000305545 7001_ $$aTräger, Isabelle$$b12
000305545 7001_ $$aZang, Chuanbing$$b13
000305545 7001_ $$aDemel, Uta M$$b14
000305545 7001_ $$aHessmann, Elisabeth$$b15
000305545 7001_ $$aKirchner, Marieluise$$b16
000305545 7001_ $$aRhein, Simone$$b17
000305545 7001_ $$aHoffmann, Jens$$b18
000305545 7001_ $$0P:(DE-He78)97a73d61ea15820362fba3e34a57f1b1$$aTatarova, Zuzana$$b19$$udkfz
000305545 7001_ $$aGhadimi, Michael$$b20
000305545 7001_ $$0P:(DE-He78)ff492c619ece40dbfbc80b938bb5deb0$$aSaur, Dieter$$b21$$udkfz
000305545 7001_ $$aKappert, Kai$$b22
000305545 7001_ $$aMertins, Philipp$$b23
000305545 7001_ $$aSchneider, Günter$$b24
000305545 7001_ $$aKeller, Ulrich$$b25
000305545 7001_ $$0P:(DE-He78)ef939d5d083b376c8fe6d4d4867a27bf$$aWirth, Matthias$$b26
000305545 773__ $$0PERI:(DE-600)1478699-0$$a10.1053/j.gastro.2025.08.018$$gp. S0016508525059037$$pnn$$tGastroenterology$$vnn$$x0016-5085$$y2025
000305545 909CO $$ooai:inrepo02.dkfz.de:305545$$pVDB
000305545 9101_ $$0I:(DE-588b)2036810-0$$6P:(DE-He78)99460bdc44722b972a7b75d603ee525a$$aDeutsches Krebsforschungszentrum$$b9$$kDKFZ
000305545 9101_ $$0I:(DE-588b)2036810-0$$6P:(DE-He78)acb61b933ca50ec93e1c11b78d3d9e62$$aDeutsches Krebsforschungszentrum$$b10$$kDKFZ
000305545 9101_ $$0I:(DE-588b)2036810-0$$6P:(DE-He78)97a73d61ea15820362fba3e34a57f1b1$$aDeutsches Krebsforschungszentrum$$b19$$kDKFZ
000305545 9101_ $$0I:(DE-588b)2036810-0$$6P:(DE-He78)ff492c619ece40dbfbc80b938bb5deb0$$aDeutsches Krebsforschungszentrum$$b21$$kDKFZ
000305545 9101_ $$0I:(DE-588b)2036810-0$$6P:(DE-He78)ef939d5d083b376c8fe6d4d4867a27bf$$aDeutsches Krebsforschungszentrum$$b26$$kDKFZ
000305545 9131_ $$0G:(DE-HGF)POF4-899$$1G:(DE-HGF)POF4-890$$2G:(DE-HGF)POF4-800$$3G:(DE-HGF)POF4$$4G:(DE-HGF)POF$$aDE-HGF$$bProgrammungebundene Forschung$$lohne Programm$$vohne Topic$$x0
000305545 9141_ $$y2025
000305545 915__ $$0StatID:(DE-HGF)0200$$2StatID$$aDBCoverage$$bSCOPUS$$d2024-12-12
000305545 915__ $$0StatID:(DE-HGF)0300$$2StatID$$aDBCoverage$$bMedline$$d2024-12-12
000305545 915__ $$0StatID:(DE-HGF)0199$$2StatID$$aDBCoverage$$bClarivate Analytics Master Journal List$$d2024-12-12
000305545 915__ $$0StatID:(DE-HGF)1050$$2StatID$$aDBCoverage$$bBIOSIS Previews$$d2024-12-12
000305545 915__ $$0StatID:(DE-HGF)0160$$2StatID$$aDBCoverage$$bEssential Science Indicators$$d2024-12-12
000305545 915__ $$0StatID:(DE-HGF)1030$$2StatID$$aDBCoverage$$bCurrent Contents - Life Sciences$$d2024-12-12
000305545 915__ $$0StatID:(DE-HGF)1190$$2StatID$$aDBCoverage$$bBiological Abstracts$$d2024-12-12
000305545 915__ $$0StatID:(DE-HGF)1110$$2StatID$$aDBCoverage$$bCurrent Contents - Clinical Medicine$$d2024-12-12
000305545 915__ $$0StatID:(DE-HGF)0113$$2StatID$$aWoS$$bScience Citation Index Expanded$$d2024-12-12
000305545 915__ $$0StatID:(DE-HGF)0150$$2StatID$$aDBCoverage$$bWeb of Science Core Collection$$d2024-12-12
000305545 915__ $$0StatID:(DE-HGF)0100$$2StatID$$aJCR$$bGASTROENTEROLOGY : 2022$$d2024-12-12
000305545 915__ $$0StatID:(DE-HGF)9925$$2StatID$$aIF >= 25$$bGASTROENTEROLOGY : 2022$$d2024-12-12
000305545 9201_ $$0I:(DE-He78)FM01-20160331$$kFM01$$lDKTK Koordinierungsstelle Frankfurt$$x0
000305545 9201_ $$0I:(DE-He78)MU01-20160331$$kMU01$$lDKTK Koordinierungsstelle München$$x1
000305545 9201_ $$0I:(DE-He78)BE01-20160331$$kBE01$$lDKTK Koordinierungsstelle Berlin$$x2
000305545 980__ $$ajournal
000305545 980__ $$aVDB
000305545 980__ $$aI:(DE-He78)FM01-20160331
000305545 980__ $$aI:(DE-He78)MU01-20160331
000305545 980__ $$aI:(DE-He78)BE01-20160331
000305545 980__ $$aUNRESTRICTED