Abstract 3322: GW4716 selectively targets multiple p53 mutant cancer models.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC The TP53 gene is the most commonly mutated gene in all cancers, with over 50% of human cancers harboring an inactivating mutation. Most frequently when p53 is mutated, the mutation occurs as a single nucleotide substitution within the DNA-binding domain. The selective advantage for retaining mutant p53 varies between cancer cells. Mutant p53 can have both gain-of-function and loss-of-function properties. Given the high frequency of p53 mutations in human cancers, understanding mutant p53 function and identifying novel therapies is a clinically relevant and important area of research. We have identified a novel pharmacological approach that selectively targets p53 mutant cancer cells across multiple cancer models using the acyl hydrazone GW4716. We have found cancer cells harboring a mutation in p53, treated with GW4716 for 24h, exhibit significantly greater cell death measured by DNA fragmentation (subG1) than p53 wild-type cells in both breast cancer and glioblastoma models. In contrast, GW4716 has little/no effect on normal (non-transformed) cells Furthermore, the mode of cell death induced by GW4716 differs between p53 wild-type and mutant cells. p53 mutants undergo a G2/M arrest, exhibit characteristics of mitotic catastrophe and ultimately apoptose in response to GW4716. MAPK signaling proteins (p38 and MK2) involved in G2/M checkpoint control, progression through mitosis, and cell death are induced by GW4716 treatment in p53 mutant cells. In contrast, p53 wild-type cells exhibit an induction of cell cycle regulatory proteins (p53 and p21) and the p53-specific autophagy marker DRAM, with a concomitant inhibition of p62 (SQSTM1). This leads us to hypothesize that the cytotoxic effects of GW4716 treatment occur in a p53-dependent manner, and the mode of cell death caused by GW4716 differs depending on p53 status. We hypothesize the loss of functional p53 leads to aberrant mitosis and ultimately apoptosis. We also hypothesize that p53 wild-type cells, which are less sensitive to GW4716, undergo autophagy. With the increasing emphasis on personalized medicine, these data suggest a clinically relevant role for GW4716 in the treatment of multiple p53 mutant cancers. Citation Format: Mary Heckler, Christopher Albanese, Rebecca Riggins. GW4716 selectively targets multiple p53 mutant cancer models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3322. doi:10.1158/1538-7445.AM2013-3322 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.