Abstract 6185: Combining PARP inhibitor with cMET Inhibition overcomes PARP inhibitor resistance in epithelial ovarian cancer

Abstract

Abstract Many studies have reported the efficacy of poly (ADP-ribose) polymerase (PARP) inhibitors in patients with epithelial ovarian cancer (EOC) with or without both germline/somatic BRCA mutations. However, resistance to PARP inhibitor occurs frequently in patients with advanced stage and recurrent. The receptor tyrosine kinase cMET, which is frequently overexpressed in EOC associates with PARP1 activity and cell survival pathway. Therefore, we investigated whether the combination of olaparib and savolitinib, a novel cMET inhibitor, could overcome PARP inhibitor resistance on resistant patient-derived xenografts (PDXs). Tumor tissues were obtained from patients with EOC operated at department of obstetrics and gynecology, Asan medical center, Seoul, South Korea. BRCA1 or BRCA2 mutated and cMET overexpressed tumors were selected and used for animal experiments. The tumor tissues were subcutaneous transplanted into right flank of NOD-scid IL2Rgammanull (NSG) mice. 60~90 days after transplantation, olaparib was administrated (80~100 mg/kg, daily, P.O.). Tumors were inhibited until volume decreased to 0~50 mm3. When the tumor volume was reached under 50 mm3, administration was stopped and tumors were allowed to regrowth. After tumor regrowth, to confirm resistance, administrated concentration of the olaparib was gradually increased 40 to 100 mg/kg (daily, P.O.). The resistant tumors were harvested and re-transplanted into 40 NSG mice. When tumor volumes reached at 100 mm3, mice were divided into 4 groups (Vehicle, Olapairb, Savolitinib, Combination) and olaparib (100 mg/kg, daily, P.O.) and savolitinib (25 mg/kg, daily, P.O.) were administrated. 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. In case of the olaparib sensitive PDXs, tumor growth was suppressed to a similar level in combination group and olaparib single treatment group. Single treatment of cMET inhibitor also showed little inhibition in tumor growth. In case of the 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. The innate resistant PDXs were more tolerated to olapairb than the acquired resistant PDXs. Similar to acquired resistant PDXs, innate PDXs also showed rapid tumor growth in vehicle. As the acquired resistant PDXs, combination treatment was most efficient to inhibited tumor growth. In this study, cMET inhibition sensitized the resistant tumor to PARP inhibitor. These results indicated that savolitinib, novel cMET inhibitor, could have synergy with the PARP inhibitor for patients with PARP inhibitor resistant ovarian cancer. Citation Format: Min-Je Kim, Shin-Wha Lee, Young-Jae Lee, Su-Bin Park, Dong-Woo Kang, Yong-Man Kim. Combining PARP inhibitor with cMET Inhibition overcomes PARP inhibitor resistance in epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6185.