Combination of olaparib and savolitinib overcomes olaparib-resistance in epithelial ovarian cancer models

Abstract

Abstract Background Resistance to PARP inhibitor occurs frequently and diversely in spite of germline/somatic BRCA mutations. Receptor tyrosine kinase cMET, which is frequently overexpressed in EOC associates with PARP1 activity and cell survival pathway. We investigated whether the combination of PARP inhibitor and cMET inhibitor could overcome PARP inhibitor resistance in resistant patient-derived xenografts (PDXs). Methods We established acquired resistant and innate resistant PDXs, which have BRCA mutation and cMET overexpression. These resistant models were used for evaluation of combined treatment of PARP inhibitor and cMET inhibitor. Resistant PDXs were treated with Vehicle, Olapairb, Savolitinib, Combination treatment. Results In acquired resistant PDXs, tumor growth rate were highly increased in vehicle group than the sensitive PDXs. Contrary to sensitive group, combination treatment was more efficient to inhibit tumor growth rather than olaparib single treatment. In the innate resistant PDXs were more tolerated to olapairb than the acquired resistant PDXs. As the acquired resistant PDXs, combination treatment was most efficient to inhibited tumor growth. Conclusion In this study, cMET inhibition sensitized the tumor with PARP inbihitor resistance to PARP inhibitor. These results indicated that savolitinib could have synerge with the combined treatment of PARP inhibitors for EOC patients with PARP inhibitor resistant.