Abstract 5455: Novel miRNA-based therapeutic approach to selectively target mutant p53 in cancer

Abstract

Abstract Tumor suppressor p53, guardian of the genome, is frequently mutated or functionally dysregulated in more than 50% of human tumors. p53 mutation is a later event in tumorigenesis and a number of p53 mutants have “Gain of Function” (GOF) properties that have been shown to promote invasive and more aggressive phenotypes in cancer cells. Mutant p53 has been an attractive and promising therapeutic target for advanced stages of tumors. Yet, mutant p53 has proved to be one of the most undruggable targets. Thus, there is continued interest in understanding the GOF properties of mutant p53 and in designing novel strategies to target mutant p53 and/or key GOF pathways. Mature MicroRNAs (miRNAs) are ~22 nt endogenous, non-coding RNA sequences that bind to 3’UTR of their target genes and inhibit their translation. miRNA mimics are emerging therapeutics and attractive tools for mapping pathway networks. We developed a novel functional high throughput screening (HTS) assay to identify miRNAs that selectively target mutant p53-expressing cell lines. The HTS was performed in isogenic TP53+/+ (wild-type), TP53-/- (null) and TP53 R175H (mutant) HCT-116 colorectal cancer cell lines. Cell viability was used as the HTS read-out of our functional screen. Of 2754 miRNA mimics screened, we identified 56 miRNAs that selectively target TP53 R175H (mutant) cells. Our ongoing work is directed to further validating and identifying which of these miRNA mimics selectively induce apoptosis in mutant p53-expressing cells. We are also using reporter-based assays to identify a fraction of the 56 miRNAs that can bind to the p53 3’UTR. Our long-term goal is to selectively target mutant p53-expressing cells using miRNA mimics as single agents or in combination with FDA-approved or experimental therapeutics. Our strategy is may provide a unique opportunity for development of targeted therapy for TP53 mutant tumors. Citation Format: Amriti R. Lulla, Margret B. Einarson, Yan Zhou, David T. Dicker, Wafik S. El-Deiry. Novel miRNA-based therapeutic approach to selectively target mutant p53 in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5455. doi:10.1158/1538-7445.AM2017-5455