Abstract 6363: Small molecule PG3-Oc partially restores the p53 pathway transcriptome and proteome in tumors with mutant p53 through ATF4 transcriptional modulation by ERK1/2 and CDK9

Abstract

Abstract The tumor-suppressor p53 prevents cancer development via initiating cell-cycle arrest, cell death, repair, or anti-angiogenesis processes. Over 50% of human cancers harbor cancer-causing mutations in p53. p53 mutations not only abrogate its tumor-suppressor function, but also endow mutant p53 with a gain of function (GOF), creating a proto-oncogene that contributes to tumorigenesis, tumor progression, and chemo- or radiotherapy resistance. Thus, targeting mutant p53 and/or restoring a wild-type p53 signaling pathway provides an attractive strategy for cancer therapy. We previously reported that prodigiosin, a natural product, has potent anti-cancer activity against tumors with mutated p53. The novel synthetic analogue of prodigiosin, PG3-Oc, is potent in reducing both short-term and long-term proliferation in a broad panel of mutant p53 cell lines. PG3-Oc treatment induces genome-wide restoration of p53 target genes, which are mediated by activation of ATF4. We demonstrate that ERK1/2 and CDK9 kinase functions are required for ATF4 transcriptional activity in mutant p53-expressing cancer cells. We have characterized a mechanism of PG3-Oc that engages the apoptosis pathway by upregulation of the pro-apoptotic p53 target gene PUMA in a time-and dose-dependent manner through the ATF4/PUMA axis in colorectal cancer cell lines. We further report the impact of PG3-Oc on the p53 transcriptome and proteome and the role of ATF4. Our results demonstrate feasibility of functional cellular reprogramming to restore p53 pathway signaling and provide novel insights into mechanisms of signaling leading to cell death and tumor suppression with potential clinical relevance in cancer therapy. Citation Format: Xiaobing Tian, Nagib Ahsan, Wafik S. El-Deiry. Small molecule PG3-Oc partially restores the p53 pathway transcriptome and proteome in tumors with mutant p53 through ATF4 transcriptional modulation by ERK1/2 and CDK9 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6363.