Abstract NT-104: SYNERGISTIC COMBINATION OF MORTALIN-TARGETING AND P53 REACTIVATOR DRUGS FOR OVARIAN CANCER

Abstract

Abstract PURPOSE: TP53 gene missense mutations represent the most common genetic defect in fallopian tube (FT) lesions and high grade serous ovarian cancer (HGSOC) and cause of drug resistance. We hypothesized that drugs with complementary p53 protein-targeted mechanisms (SHetA2 drug release of p53 from mortalin binding, PRIMA-1MET drug reactivation of p53 transcription activity) synergistically kill ovarian cancer cells without harming normal cells. EXPERIMENTAL DESIGN: SHetA2-mediated cytoplasmic to nuclear/mitochondrial p53 translocation was studied in wildtype and mutant p53 ovarian cancer cell lines using Western blot analysis of subcellular-enriched fractions and fluorescent microscopic imaging of immunocytochemistry. Human FT epithelial cells (hFTSECs) were used as healthy controls. The p53 reactivator drugs PRIMA-1 and PRIMA-1MET were combined with SHetA2 to study drug interactions and mechanisms using Western blot, rtPCR, cytotoxicity, reactive oxygen species (ROS) and ATP assays. RESULTS: SHetA2 induced p53 nuclear and mitochondrial accumulation in ovarian cancer cell lines, but not in hFTSECs. Both mortalin and p53 expression altered SHetA2 cytotoxicity in ovarian cancer cells. Modest effects of PRIMA-1MET on cell lines inversely correlated with SLC7A11 expression, a known biomarker of PRIMA-1MET sensitivity. SHetA2 induced SLC7A11 in the presence of wildtype or missense mutant p53, but inhibited SLC7A11 in the absence of p53. SHetA2 and PRIMA-1MET were synergistic-to-strongly synergistic in ovarian cancer cells with mutant p53, synergistic with wildtype p53, additive with null p53 and antagonistic in hFTSECs. Elevated apoptosis, p53 transcription activity and ROS in combination with reduced ATP were associated with this mutant p53-dependent synergy. CONCLUSION: Altogether, our findings identified the SHetA2 and PRIMA-1MET combination as a promising new therapeutic strategy for the treatment of HGSOCs with missense mutant p53. GRANT SUPPORT: Supported by the US National Cancer Institute grant R01 CA196200 and Foundation for Women's Cancer- Ovarinnovate: Ovarcome Research Excellence Award. Citation Format: Satish Kumar Ramraj, Doris M. Benbrook. SYNERGISTIC COMBINATION OF MORTALIN-TARGETING AND P53 REACTIVATOR DRUGS FOR OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-104.