Inhibition of the Cyclin K-CDK12 complex induces DNA damage and increases the effect of androgen deprivation therapy in prostate cancer

dc.contributor.authorFrei, Katahrina
dc.contributor.authorSchechter, Sabrina
dc.contributor.authorDaher, Tamas
dc.contributor.authorHörner, Nina
dc.contributor.authorRichter, Jutta
dc.contributor.authorHildebrand, Ute
dc.contributor.authorSchindeldecker, Mario
dc.contributor.authorWitzel, Hagen R.
dc.contributor.authorTsaur, Igor
dc.contributor.authorPorubsky, Stefan
dc.contributor.authorGaida, Matthias M.
dc.contributor.authorRoth, Wilfried
dc.contributor.authorTagscherer, Katrin E.
dc.date.accessioned2024-01-18T08:15:14Z
dc.date.available2024-01-18T08:15:14Z
dc.date.issued2023
dc.description.abstractAndrogen deprivation therapy (ADT) is the mainstay of the current first-line treatment concepts for patients with advanced prostate carcinoma (PCa). However, due to treatment failure and recurrence investigation of new targeted therapeutics is urgently needed. In this study, we investigated the suitability of the Cyclin K-CDK12 complex as a novel therapeutic approach in PCa using the new covalent CDK12/13 inhibitor THZ531. Here we show that THZ531 impairs cellular proliferation, induces apoptosis, and decreases the expression of selected DNA repair genes in PCa cell lines, which is associated with an increasing extent of DNA damage. Furthermore, combination of THZ531 and ADT leads to an increase in these anti-tumoral effects in androgen-sensitive PCa cells. The anti-proliferative and pro-apoptotic activity of THZ531 in combination with ADT was validated in an ex vivo PCa tissue culture model. In a retrospective immunohistochemical analysis of 300 clinical tissue samples we show that Cyclin K (CycK) but not CDK12 expression correlates with a more aggressive type of PCa. In conclusion, this study demonstrates the clinical relevance of the CycK-CDK12 complex as a promising target for combinational therapy with ADT in PCa and its importance as a prognostic biomarker for patients with PCa.en_GB
dc.identifier.doihttp://doi.org/10.25358/openscience-9762
dc.identifier.urihttps://openscience.ub.uni-mainz.de/handle/20.500.12030/9780
dc.language.isoengde
dc.rightsCC-BY-4.0*
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/*
dc.subject.ddc610 Medizinde_DE
dc.subject.ddc610 Medical sciencesen_GB
dc.titleInhibition of the Cyclin K-CDK12 complex induces DNA damage and increases the effect of androgen deprivation therapy in prostate canceren_GB
dc.typeZeitschriftenaufsatzde
jgu.journal.titleInternational journal of cancerde
jgu.journal.volumeVersion of Record (VoR)de
jgu.organisation.departmentFB 04 Medizinde
jgu.organisation.nameJohannes Gutenberg-Universität Mainz
jgu.organisation.number2700
jgu.organisation.placeMainz
jgu.organisation.rorhttps://ror.org/023b0x485
jgu.publisher.doi10.1002/ijc.34778de
jgu.publisher.issn0020-7136de
jgu.publisher.nameWiley-Lissde
jgu.publisher.placeBognor Regisde
jgu.publisher.year2023
jgu.rights.accessrightsopenAccess
jgu.subject.ddccode610de
jgu.subject.dfgLebenswissenschaftende
jgu.type.dinitypeArticleen_GB
jgu.type.resourceTextde
jgu.type.versionPublished versionde

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