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000306238 0247_ $$2ISSN$$a2159-8290
000306238 037__ $$aDKFZ-2025-02467
000306238 041__ $$aEnglish
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000306238 1001_ $$00000-0002-4158-5549$$aStossel, Chani$$b0
000306238 245__ $$aSpectrum of Response to Platinum and PARP Inhibitors in Germline BRCA-Associated Pancreatic Cancer in the Clinical and Preclinical Setting.
000306238 260__ $$aPhiladelphia, Pa.$$b[Verlag nicht ermittelbar]$$c2023
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000306238 520__ $$aGermline BRCA-associated pancreatic ductal adenocarcinoma (glBRCA PDAC) tumors are susceptible to platinum and PARP inhibition. The clinical outcomes of 125 patients with glBRCA PDAC were stratified based on the spectrum of response to platinum/PARP inhibition: (i) refractory [overall survival (OS) <6 months], (ii) durable response followed by acquired resistance (OS <36 months), and (iii) long-term responders (OS >36 months). Patient-derived xenografts (PDX) were generated from 25 patients with glBRCA PDAC at different clinical time points. Response to platinum/PARP inhibition in vivo and ex vivo culture (EVOC) correlated with clinical response. We deciphered the mechanisms of resistance in glBRCA PDAC and identified homologous recombination (HR) proficiency and secondary mutations restoring partial functionality as the most dominant resistant mechanism. Yet, a subset of HR-deficient (HRD) patients demonstrated clinical resistance. Their tumors displayed basal-like molecular subtype and were more aneuploid. Tumor mutational burden was high in HRD PDAC and significantly higher in tumors with secondary mutations. Anti-PD-1 attenuated tumor growth in a novel humanized glBRCA PDAC PDX model. This work demonstrates the utility of preclinical models, including EVOC, to predict the response of glBRCA PDAC to treatment, which has the potential to inform time-sensitive medical decisions.glBRCA PDAC has a favorable response to platinum/PARP inhibition. However, most patients develop resistance. Additional treatment options for this unique subpopulation are needed. We generated model systems in PDXs and an ex vivo system (EVOC) that faithfully recapitulate these specific clinical scenarios as a platform to investigate the mechanisms of resistance for further drug development. This article is highlighted in the In This Issue feature, p. 1749.
000306238 588__ $$aDataset connected to CrossRef, PubMed, , Journals: inrepo02.dkfz.de
000306238 650_7 $$2NLM Chemicals$$aPoly(ADP-ribose) Polymerase Inhibitors
000306238 650_7 $$049DFR088MY$$2NLM Chemicals$$aPlatinum
000306238 650_2 $$2MeSH$$aHumans
000306238 650_2 $$2MeSH$$aPoly(ADP-ribose) Polymerase Inhibitors: pharmacology
000306238 650_2 $$2MeSH$$aPoly(ADP-ribose) Polymerase Inhibitors: therapeutic use
000306238 650_2 $$2MeSH$$aPlatinum: pharmacology
000306238 650_2 $$2MeSH$$aPlatinum: therapeutic use
000306238 650_2 $$2MeSH$$aPancreatic Neoplasms: drug therapy
000306238 650_2 $$2MeSH$$aPancreatic Neoplasms: genetics
000306238 650_2 $$2MeSH$$aMutation
000306238 650_2 $$2MeSH$$aCarcinoma, Pancreatic Ductal: drug therapy
000306238 650_2 $$2MeSH$$aCarcinoma, Pancreatic Ductal: genetics
000306238 7001_ $$00000-0002-5763-224X$$aRaitses-Gurevich, Maria$$b1
000306238 7001_ $$00000-0003-3362-025X$$aAtias, Dikla$$b2
000306238 7001_ $$00009-0004-2051-6415$$aBeller, Tamar$$b3
000306238 7001_ $$00000-0003-2106-505X$$aGlick Gorman, Yulia$$b4
000306238 7001_ $$00009-0001-8160-9429$$aHalperin, Sharon$$b5
000306238 7001_ $$00000-0002-2034-1625$$aPeer, Eyal$$b6
000306238 7001_ $$00000-0003-2197-7083$$aDenroche, Robert E$$b7
000306238 7001_ $$00000-0002-6536-3609$$aZhang, Amy$$b8
000306238 7001_ $$00000-0002-5748-3985$$aNotta, Faiyaz$$b9
000306238 7001_ $$00000-0003-2510-962X$$aWilson, Julie M$$b10
000306238 7001_ $$00000-0002-8690-403X$$aO'Kane, Grainne M$$b11
000306238 7001_ $$00009-0006-4513-6843$$aHaimov Talmoud, Elina$$b12
000306238 7001_ $$00000-0001-5811-4391$$aAmison, Nora$$b13
000306238 7001_ $$00009-0001-9694-4596$$aSchvimer, Michael$$b14
000306238 7001_ $$00000-0002-6960-2419$$aSalpeter, Seth J$$b15
000306238 7001_ $$00009-0005-6601-7424$$aBar, Vered$$b16
000306238 7001_ $$00000-0001-6629-3588$$aZundelevich, Adi$$b17
000306238 7001_ $$00000-0001-5477-2987$$aTirosh, Itay$$b18
000306238 7001_ $$00009-0005-3703-2393$$aTal, Rotem$$b19
000306238 7001_ $$00009-0004-3942-9629$$aDinstag, Gal$$b20
000306238 7001_ $$00009-0002-1013-1330$$aKinar, Yaron$$b21
000306238 7001_ $$00009-0002-0515-7579$$aEliezer, Yonatan$$b22
000306238 7001_ $$00000-0001-7098-2378$$aBen-David, Uri$$b23
000306238 7001_ $$00000-0003-1639-4684$$aGavert, Nancy S$$b24
000306238 7001_ $$00000-0002-9476-329X$$aStraussman, Ravid$$b25
000306238 7001_ $$00000-0002-6998-9414$$aGallinger, Steven J$$b26
000306238 7001_ $$00000-0002-2788-0971$$aBerger, Raanan$$b27
000306238 7001_ $$00000-0001-5939-7012$$aGolan, Talia$$b28
000306238 773__ $$0PERI:(DE-600)2607892-2$$a10.1158/2159-8290.CD-22-0412$$gVol. 13, no. 8, p. 1826 - 1843$$n8$$p1826 - 1843$$tCancer discovery$$v13$$x2159-8274$$y2023
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