Abstract 2643: Small molecule identification for the restoration of p53 pathway through p73 and by degradation of mutant p53

Abstract

Abstract One of the most explored cancer targets has been the tumor suppressor p53. p53 is mutated in more than half of all human tumors and therefore provides an attractive way to selectively target cancer cells that harbor the mutant protein. Mutant p53 protein can acquire a gain-of-function activity, losing its normal tumor suppressor properties and gaining oncogenic characteristics. Various approaches have been taken to restore the p53 pathway in mutant p53 expressing cells including the modulation of mutant p53 conformation to wild-type, and through the upregulation of p53 family members i.e. p73. Unlike p53, p73 is not commonly mutated in cancer cells and thus confers restoration of the p53 pathway through pharmacological stimulation. We characterized a small molecule that restores the p53 pathway through p73. A high-throughput cell-based screen identified small molecule CB002 as a potential candidate for the restoration of the p53 pathway in mutant p53 containing human colorectal cancer cells. Two colorectal cancer cell lines: SW480, DLD-1, and the RXF393 renal cancer cell line, were treated with different concentrations of CB002 for various time points. SW480 cells treated with CB002 for 8 hrs showed a decrease in p53 followed by an increase in DR5 expression at 16 hrs. DLD-1 cells treated with CB002 showed a decrease in p53 expression at 8 hrs. Although no change was observed in proteins involved in cell cycle arrest or cell death that were tested, colony formation was suppressed as compared to control. RXF393 cells treated with CB002 for 48 hrs showed decreased expression of p53 levels and increased levels of p21. These data suggest that CB002 is able to decrease mutant p53 protein expression, increase p53 target genes and promote expression of proteins involved in apoptosis, such as p21 and DR5, respectively. It appears that the CB002 mechanism is different depending on the cell line tested. We hypothesize that CB002 is capable of degrading mutant p53 and restoring the p53 pathway through p73 in colorectal cancer cells. Current undergoing experiments are focused on unraveling the p73 dependence through p73 knockdown and the mechanism of action involved in each cell line. The following project will aid in the understanding of the role of p73 in pharmacological restoration of the p53 pathway in cancer therapy. Citation Format: Liz J. Hernandez Borrero, Shengliang Zhao, David T. Dicker, Wafik El-Deiry. Small molecule identification for the restoration of p53 pathway through p73 and by degradation of mutant p53. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2643. doi:10.1158/1538-7445.AM2015-2643