TY  - JOUR
AU  - Klotz, Daniel Martin
AU  - Schwarz, Franziska Maria
AU  - Dubrovska, Anna
AU  - Schuster, Kati
AU  - Theis, Mirko
AU  - Krüger, Alexander
AU  - Kutz, Oliver
AU  - Link, Theresa
AU  - Wimberger, Pauline
AU  - Drukewitz, Stephan
AU  - Buchholz, Frank
AU  - Thomale, Jürgen
AU  - Kuhlmann, Jan Dominik
TI  - Establishment and Molecular Characterization of an In Vitro Model for PARPi-Resistant Ovarian Cancer.
JO  - Cancers
VL  - 15
IS  - 15
SN  - 2072-6694
CY  - Basel
PB  - MDPI
M1  - DKFZ-2023-01644
SP  - 3774
PY  - 2023
AB  - 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.
KW  - PARPi resistance (Other)
KW  - cisplatin (Other)
KW  - ovarian cancer (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:37568590
C2  - pmc:PMC10417418
DO  - DOI:10.3390/cancers15153774
UR  - https://inrepo02.dkfz.de/record/278410
ER  -