Preclinical in vitro and in vivo evaluation of antitumor activity of poly (ADP-ribose) polymerase inhibition and trastuzumab combined therapy in HER2-overexpressing breast cancer.

622 Background: PARP inhibitors have provided promising results in BRCA deficient breast cancer, but not in unselected patient populations. Two lines of research in this field are needed: identification of novel subsets of patients that could potentially benefit from PARP inhibitors and the discovery of suitable targeted therapies for combination strategies. Methods: We tested PARP inhibition, alone or combined with the anti-HER2 antibody trastuzumab on HER2 positive breast cancer. We used two PARP inhibitors in clinical development, olaparib and rucaparib, as well as genetic downmodulation of PARP-1 for in vitro studies. DNA damage was studied by the formation of γH2AX foci and comet assay. Finally, in vivo anti-tumor effect of olaparib and trastuzumab was examined in subcutaneously implanted BT474 cells in nude mice. Results: In a panel of four HER2 overexpressing cell lines, but not in non-HER2 overexpressing breast cancer cell lines, both olaparib and rucaparib significantly decreased cell growth and ...