Abstract 3358: Targeting p63 isoforms in cancer to restore their anti-tumorigenic activity

Abstract

Abstract p63 plays a central role in limb formation and epithelial differentiation. p63, reported to correlate with cancer formation, is rarely mutated in cancers. Different p63 isoforms can have anti-tumorigenic or pro-tumorigenic activity. TA isoforms act as tumor suppressor by promoting cell death, while deltaN isoforms are strong driver for squamous/squamous-like cancers including lung, head and neck, cervical, skin and pancreas. A large number of tumors are addicted to deltaN isoforms. Furthermore, cancer associated p53R175H mutant gains ability to interact with TAp63 isoforms and inhibit their anti-tumorigenic function, while indirectly promoting tumorigenic function of deltaN isoforms. However, the exact mechanism of p53R175H-p63 interaction is unclear. The changes in the balance of p63 isoform activity are likely to be crucial to understanding the transition between normal cell and tumor formation. Here, we modelled p53R175H-p63 complex using homology modelling, flexible/unbiased docking and molecular dynamics simulations. Moreover, we used our models to design peptides to disrupt p53R175H-p63 interaction and restore anti-tumorigenic function of TAp63 isoforms. Also, we studied deltaN isoform oligomerization and designed peptides to inhibit their oligomerization to reduce their tumorigenic activity. We showed that some of our peptides promoted cell death in a p63 enriched cancel cell line. We characterized our peptides performing kinetic binding assays to validate binding of our peptides to their designated targets. In this study, our computational and experimental analyses presented a detailed model for the p53R175H-p63 interaction. We also provided a framework for potential therapeutic peptides to outweigh the balance in the advantage of anti-tumorigenic p63 activity. Citation Format: E. Sila Ozdemir, Michelle Gomes, Jared Fischer. Targeting p63 isoforms in cancer to restore their anti-tumorigenic activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3358.