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FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy

Fisch KM; Sulzmaier FJ; Barrie AM; Chen XL; Ojalill M; Gyorffy B; Taylor KN; Xu GR; McHale MT; Uryu S; Fu G; Osterman CJD; Anderson K; Heino J; Ozmadenci D; Weaver DT; Bean LM; Cordasco EA; Molinolo A; Connolly DC; Pachter JA; Jean C; Kolev VN; Mark AM; Kleinschmidt EG; Jiang SL; Li J; Tancioni I; Rappu P; Stupack DG; Schlaepfer DD

dc.contributor.authorFisch KM
dc.contributor.authorSulzmaier FJ
dc.contributor.authorBarrie AM
dc.contributor.authorChen XL
dc.contributor.authorOjalill M
dc.contributor.authorGyorffy B
dc.contributor.authorTaylor KN
dc.contributor.authorXu GR
dc.contributor.authorMcHale MT
dc.contributor.authorUryu S
dc.contributor.authorFu G
dc.contributor.authorOsterman CJD
dc.contributor.authorAnderson K
dc.contributor.authorHeino J
dc.contributor.authorOzmadenci D
dc.contributor.authorWeaver DT
dc.contributor.authorBean LM
dc.contributor.authorCordasco EA
dc.contributor.authorMolinolo A
dc.contributor.authorConnolly DC
dc.contributor.authorPachter JA
dc.contributor.authorJean C
dc.contributor.authorKolev VN
dc.contributor.authorMark AM
dc.contributor.authorKleinschmidt EG
dc.contributor.authorJiang SL
dc.contributor.authorLi J
dc.contributor.authorTancioni I
dc.contributor.authorRappu P
dc.contributor.authorStupack DG
dc.contributor.authorSchlaepfer DD
dc.date.accessioned2022-10-28T13:33:39Z
dc.date.available2022-10-28T13:33:39Z
dc.identifier.urihttps://www.utupub.fi/handle/10024/166029
dc.description.abstractGene copy number alterations, tumor cell stemness, and the development of platinum chemotherapy resistance contribute to high-grade serous ovarian cancer (HGSOC) recurrence. Stem phenotypes involving Wnt-beta-catenin, aldehyde dehydrogenase activities, intrinsic platinum resistance, and tumorsphere formation are here associated with spontaneous gains in Kras, Myc and FAK (KMF) genes in a new aggressive murine model of ovarian cancer. Adhesion-independent FAK signaling sustained KMF and human tumorsphere proliferation as well as resistance to cisplatin cytotoxicity. Platinum-resistant tumorspheres can acquire a dependence on FAK for growth. Accordingly, increased FAK tyrosine phosphorylation was observed within HGSOC patient tumors surviving neo-adjuvant chemotherapy. Combining a FAK inhibitor with platinum overcame chemoresistance and triggered cell apoptosis. FAK transcriptomic analyses across knockout and reconstituted cells identified 135 targets, elevated in HGSOC, that were regulated by FAK activity and beta-catenin including Myc, pluripotency and DNA repair genes. These studies reveal an oncogenic FAK signaling role supporting chemoresistance.
dc.language.isoen
dc.publisherELIFE SCIENCES PUBLICATIONS LTD
dc.titleFAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy
dc.identifier.urnURN:NBN:fi-fe2021042827686
dc.relation.volume8
dc.contributor.organizationfi=PÄÄT Biokemia|en=PÄÄT Biochemistry|
dc.contributor.organization-code2606201
dc.converis.publication-id42614756
dc.converis.urlhttps://research.utu.fi/converis/portal/Publication/42614756
dc.identifier.eissn2050-084X
dc.identifier.jour-issn2050-084X
dc.okm.affiliatedauthorOjalill, Marjaana
dc.okm.affiliatedauthorHeino, Jyrki
dc.okm.affiliatedauthorRappu, Pekka
dc.okm.discipline3111 Biolääketieteetfi_FI
dc.okm.discipline3111 Biomedicineen_GB
dc.okm.internationalcopublicationinternational co-publication
dc.okm.internationalityInternational publication
dc.okm.typeJournal article
dc.publisher.countryUnited Kingdomen_GB
dc.publisher.countryBritanniafi_FI
dc.publisher.country-codeGB
dc.relation.articlenumberARTN e47327
dc.relation.doi10.7554/eLife.47327
dc.relation.ispartofjournaleLife
dc.year.issued2019


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