The Poly (Adp-Ribose) Polymerase Inhibitor Olaparib and Pan-Erbb Inhibitor Neratinib Are Highly Synergistic in HER2 Overexpressing Epithelial Ovarian Carcinoma in Vitro and in Vivo

Introduction. Ovarian cancer (OC) is associated with the highest gynecologic cancer mortality. The develop-ment of novel, effective combinations of targeted therapeutics remains an unmet medical need. We evaluated the preclinical efficacy of the Poly (ADP-ribose) polymerase (PARP) inhibitor (olaparib) and the pan-ErbB inhib-itor (neratinib) as single agents and in combination in ovarian cancer cell lines and xenografts with variable HER2 expression.Methods. In vitro cell viability with olaparib, neratinib, and their combination was assessed using flow-cytometry based assays against a panel of OC primary cell lines with variable HER2 expression. Immunoblotting experiments were performed to elucidate the mechanism of activity and synergism. The in vivo antitumor activ-ity of the olaparib/neratinib combination versus single agents was tested in HER2 positive xenograft OC models. Results. HER2 + OC cell lines demonstrated higher sensitivity to olaparib and neratinib when compared to HER2 negative tumors (i.e., IC50: 2.06 +/- 0.33 JIM vs. 39.28 +/- 30.51 JIM, p = 0.0035 for olaparib and 19.42 +/- 2.63 nM vs. 235.0 +/- 165.0 nM, p = 0.0035 for neratinib). The combination of olaparib with neratinib was more potent when compared to single-agent olaparib or neratinib both in vitro and in vivo, and demonstrated synergy in all primary HER2 + OC models. Western blot experiments showed neratinib decreased pHER2/neu while increased Poly(ADP-ribose) (PAR) enzymatic activity; olaparib increased pHER2/Neu expression and blocked PAR activatio. Olaparib/neratinib in combination decreased both pHER2/Neu as well as PAR activation.Conclusion. The combination of olaparib and neratinib is synergistic and endowed with remarkable preclinical activity against HER2+ ovarian cancers. This combination may represent a novel therapeutic option for ovarian cancer patients with HER2+, homologous recombination-proficient tumors resistant to chemotherapy.(c) 2023 Published by Elsevier Inc.