Karkampouna, SofiaSofiaKarkampounaLa Manna, FedericoFedericoLa MannaBenjak, AndrejAndrejBenjakKiener, Mirjam SusannaMirjam SusannaKienerDe Menna, MartaMartaDe MennaZoni, EugenioEugenioZoniGrosjean, JoëlJoëlGrosjeanKlima, IrenaIrenaKlimaGarofoli, AndreaAndreaGarofoliBolis, MarcoMarcoBolisVallerga, AriannaAriannaVallergaTheurillat, Jean-PhilippeJean-PhilippeTheurillatDe Filippo, Maria RosariaMaria RosariaDe FilippoGenitsch Gratwohl, VeraVeraGenitsch Gratwohl0000-0003-0919-7295Keller, DavidDavidKellerBooij, Tijmen HTijmen HBooijStirnimann, Christian UChristian UStirnimannEng, KennethKennethEngSboner, AndreaAndreaSbonerNg, Kiu Yan CharlotteKiu Yan CharlotteNgPiscuoglio, SalvatoreSalvatorePiscuoglioGray, Peter CPeter CGraySpahn, MartinMartinSpahnRubin, Mark AndrewMark AndrewRubinThalmann, GeorgeGeorgeThalmannKruithof-de Julio, MariannaMariannaKruithof-de Julio2024-09-212024-09-212021-02-18https://boris-portal.unibe.ch/handle/20.500.12422/45810Therapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe an androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naïve, soft tissue metastasis (PNPCa). RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harbors BRCA2 and CHD1 somatic mutations, shows an SPOP/FOXA1-like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modeled in vivo. Comparison of the treatment-naïve PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX- and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds. This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds.en600 - Technology::610 - Medicine & health500 - Science::570 - Life sciences; biologyarticle10.48350/1596743360291910.1038/s41467-021-21300-6