Targeting Post-Translational Regulation of p53 in Colorectal Cancer by Exploiting Vulnerabilities in the p53-MDM2 Axis

SIMPLE SUMMARY: p53, a critical tumor suppressor, is commonly mutated in neoplasia, including colorectal cancer. To devise anti-cancer strategies targeting p53, it is crucial to understand the myriad cell-specific regulatory mechanisms in the p53 signaling pathway, and how these same regulatory mechanisms may be evaded by p53 mutants. This review focuses on colorectal cancer and considers the regulatory mechanisms underlying the actions of wild type p53 protein, emphasizing discoveries made in the last decade. We focus on the role of mouse double minute 2 homolog (MDM2), which modulates p53 protein levels by targeting p53 for protein degradation; other MDM2-independent mechanisms are also discussed. These regulatory mechanisms are further examined in the context of p53 missense mutants, which can evade canonical regulation. Lastly, we consider potential strategies for therapeutic targeting of p53 mutant-bearing cancers in preclinical testing or early-phase clinical trials. ABSTRACT: The role played by the key tumor suppressor gene p53 and the implications of p53 mutations for the development and progression of neoplasia continue to expand. This review focuses on colorectal cancer and the regulators of p53 expression and activity identified over the past decade. These newly recognized regulatory mechanisms include (1) direct regulation of mouse double minute 2 homolog (MDM2), an E3 ubiquitin-protein ligase; (2) modulation of the MDM2-p53 interaction; (3) MDM2-independent p53 degradation; and (4) inhibition of p53 nuclear translocation. We positioned these regulatory mechanisms in the context of p53 missense mutations, which not only evade canonical p53 degradation machinery but also exhibit gain-of-function phenotypes that enhance tumor survival and metastasis. Lastly, we discuss current and potential therapeutic strategies directed against p53 mutant-bearing tumors.