%0 Journal Article
%A Klotz, Daniel Martin
%A Schwarz, Franziska Maria
%A Dubrovska, Anna
%A Schuster, Kati
%A Theis, Mirko
%A Krüger, Alexander
%A Kutz, Oliver
%A Link, Theresa
%A Wimberger, Pauline
%A Drukewitz, Stephan
%A Buchholz, Frank
%A Thomale, Jürgen
%A Kuhlmann, Jan Dominik
%T Establishment and Molecular Characterization of an In Vitro Model for PARPi-Resistant Ovarian Cancer.
%J Cancers
%V 15
%N 15
%@ 2072-6694
%C Basel
%I MDPI
%M DKFZ-2023-01644
%P 3774
%D 2023
%X Overcoming PARPi resistance is a high clinical priority. We established and characterized comparative in vitro models of acquired PARPi resistance, derived from either a BRCA1-proficient or BRCA1-deficient isogenic background by long-term exposure to olaparib. While parental cell lines already exhibited a certain level of intrinsic activity of multidrug resistance (MDR) proteins, resulting PARPi-resistant cells from both models further converted toward MDR. In both models, the PARPi-resistant phenotype was shaped by (i) cross-resistance to other PARPis (ii) impaired susceptibility toward the formation of DNA-platinum adducts upon exposure to cisplatin, which could be reverted by the drug efflux inhibitors verapamil or diphenhydramine, and (iii) reduced PARP-trapping activity. However, the signature and activity of ABC-transporter expression and the cross-resistance spectra to other chemotherapeutic drugs considerably diverged between the BRCA1-proficient vs. BRCA1-deficient models. Using dual-fluorescence co-culture experiments, we observed that PARPi-resistant cells had a competitive disadvantage over PARPi-sensitive cells in a drug-free medium. However, they rapidly gained clonal dominance under olaparib selection pressure, which could be mitigated by the MRP1 inhibitor MK-751. Conclusively, we present a well-characterized in vitro model, which could be instrumental in dissecting mechanisms of PARPi resistance from HR-proficient vs. HR-deficient background and in studying clonal dynamics of PARPi-resistant cells in response to experimental drugs, such as novel olaparib-sensitizers.
%K PARPi resistance (Other)
%K cisplatin (Other)
%K ovarian cancer (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:37568590
%2 pmc:PMC10417418
%R 10.3390/cancers15153774
%U https://inrepo02.dkfz.de/record/278410