Insights into combined adhesion-mediated and acquired resistance of ovarian cancer cells to PARP inhibitors highlight ERK as a target for sensitization

Purpose Cell adhesion-mediated drug resistance (CAM-DR) is a major reason for therapy failure in oncology. Its relevance for treating acquired PARP inhibitor (PARPi)-resistant ovarian cancer cells has barely been evaluated so far. Methods PARPi-resistant W1NR cells were established by treatment of the ovarian cancer cell line W1 with incrementally increasing niraparib concentrations. Cell viability was measured by MTT and annexin V/PI apoptosis assays. Flow cytometry was applied for cell cycle analysis and Western blots for detecting protein levels. Changes in cell surface composition were evaluated via FTIR spectroscopy. Results Cultivation on collagen type 1 (COL1) had complex effects on cell sensitivity to PARPi in a series of ovarian cancer cells, which were not related to cell adhesion proteins integrin β1 and DDR1. COL1 enhanced DNA repair protein expression in W1 and cisplatin-resistant W1CR cells, differing from W1NR cell behavior. Contrary to PARPi-naïve cells, COL1 did not further enhance PARPi resistance in W1NR cells. While inhibition of ATR or ATM sensitized W1NR cells to the PARPi niraparib and olaparib in absence of COL1, COL1-cultivation negated the effectiveness of this combination treatment. However, ERK was identified as a promising target to overcome acquired PARPi resistance, independent of COL1-mediated CAM-DR. Conclusion Our findings address for the first time the phenomenon of COL1-mediated CAM-DR in ovarian cancer with acquired PARPi resistance. Although COL1 impairs sensitization to PARPi by targeting the DNA repair kinases ATR and ATM, inhibition of ERK1/2 appears as key-strategy for overcoming combined CAM-DR and acquired PARPi resistance.