Cancers, Vol. 15, Pages 3774: Establishment and Molecular Characterization of an In Vitro Model for PARPi-Resistant Ovarian Cancer

Cancers, Vol. 15, Pages 3774: Establishment and Molecular Characterization of an In Vitro Model for PARPi-Resistant Ovarian Cancer Cancers doi: 10.3390/cancers15153774 Authors: Daniel Martin Klotz Franziska Maria Schwarz Anna Dubrovska Kati Schuster Mirko Theis Alexander Krüger Oliver Kutz Theresa Link Pauline Wimberger Stephan Drukewitz Frank Buchholz Jürgen Thomale Jan Dominik Kuhlmann 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-resista...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research