Abstract B210: BET inhibitors show superior ability to suppress the progression of tumors containing the Pro47Ser single-nucleotide polymorphism of p53

Abstract

Abstract The tumor suppressor TP53 is the most frequently mutated gene in human cancer and serves to restrict both tumor initiation and progression. Single-nucleotide polymorphisms (SNPs) in the p53 pathway can have a marked impact on p53 tumor suppressor function, and several have been associated with increased cancer risk. We have reported that a naturally occurring SNP affects codon 47 of TP53 (rs1800371, G/A). In most individuals, codon 47 encodes a proline (P47). However, approximately 2.5% of African-Americans express a p53 allele with a serine residue (S47) at this position. In order to compare the ability of the WT and S47 variants of p53 to suppress tumor development, we isolated mouse embryonic fibroblasts (MEFs) from WT and S47 mice and transformed them with the oncogenes E1A and Ras, in order to generate a facile model that would allow us to study responses to therapy. WT and S47 cells grew similarly in 10% serum. However, transformed S47 cells grew significantly better under nutrient-deprived conditions. S47 transformed cells also grew with increased dynamics in a xenograft mouse model and in a tail vein model of metastasis. These data support the premise that the S47 variant of p53 is significantly impaired as a tumor suppressor. We found that, for the majority of conventional genotoxic drugs, S47 tumor cells are resistant, compared to tumor cells with WT p53. In order to identify novel compounds that preferentially target S47 tumor cells, we performed a drug screen on WT and S47 transformed MEFs, using a library of over 200 conventional and experimental chemotherapeutic drugs. We found that S47 cells are far more sensitive to the class of bromodomain inhibitors, specifically BET inhibitors. Using short-term (96 hrs, Alamar Blue) cell viability assays, we found that S47 transformed cells were approximately 5-fold more sensitive to OTX-015, a BET inhibitor currently in clinical trials. We also found that S47 cells were significantly impaired in their ability to form colonies when pretreated for 24 hours with OTX-015. These data highlight the relevance of targeted therapy for patients harboring the S47 variant of p53, and suggest that BET inhibitors may preferentially target S47 tumors. Citation Format: Thibaut Barnoud, Subhasree Basu, Che-Pei Kung, Matthew Reiss, Rugang Zhang, Maureen Murphy. BET inhibitors show superior ability to suppress the progression of tumors containing the Pro47Ser single-nucleotide polymorphism of p53 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B210.