PARP inhibitor olaparib has a potential to increase the effectiveness of electrochemotherapy in BRCA1 mutated breast cancer in mice

Electrochemotherapy (ECT), a local therapy, has different effectiveness among tumor types. In breast cancer, its effectiveness is low; therefore, combined therapies are needed. The aim of our study was to combine ECT with PARP inhibitor olaparib, which could inhibit the repair of bleomycin or cisplatin induced DNA damage and potentiate the effectiveness of ECT. The effects of combined therapy were studied in BRCA1 mutated (HCC1937) and non-mutated (HCC1143) triple negative breast cancer cell lines. Therapeutic effectiveness was studied in 2D and 3D cell cultures and in vivo on subcutaneous HCC1937 tumor model in mice. The underlying mechanism of combined therapy was determined with the evaluation of γH2AX foci. Combined therapy of ECT with bleomycin and olaparib potentiated the effectiveness of ECT in BRCA1 mutated HCC1937, but not in non-mutated HCC1143 cells. The combined therapy had a synergistic effect, which was due to the increased number of DNA double strand breaks. Addition of olaparib to ECT with bleomycin in vivo in HCC1937 tumor model had only minimal effect, indicating repetitive olaparib treatment would be needed. This study demonstrates that DNA repair inhibiting drugs, like olaparib, have the potential to increase the effectiveness of ECT with bleomycin.