Targeting mutant p53 in cancer: a long road to precision therapy

• Published in: The FEBS journal Vol. 284; no. 6; pp. 837 - 850
• Main Authors: Mantovani, Fiamma, Walerych, Dawid, Sal, Giannino Del
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.03.2017
• Subjects: Animal models; Animals; Cancer; Cancer therapies; Cell culture; Chromatin; gain‐of‐function; Gene Expression Regulation, Neoplastic - genetics; Gene regulation; Genes; Humans; Metabolic pathways; Mice; MicroRNAs; MicroRNAs - genetics; miRNA; missense mutant p53; Molecular Targeted Therapy; Mutant Proteins - genetics; Mutant Proteins - therapeutic use; Mutation; Neoplasms - genetics; Neoplasms - therapy; oncogenic signaling; p53 Protein; Precision Medicine; precision therapy; Proteins; Proteomes; Ribonucleic acid; RNA; Signal Transduction; Transcription; tumor environment; Tumor suppressor genes; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - therapeutic use; Tumorigenesis; Tumors; tumor environment; oncogenic signaling; gain-of-function; missense mutant p53; precision therapy
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.13948

The TP53 tumor suppressor is the most frequently mutated gene in human cancers. In recent years, a blooming of research efforts based on both cell lines and mouse models have highlighted how deeply mutant p53 proteins affect fundamental cellular pathways with cancer‐promoting outcomes. Neomorphic mutant p53 activities spread over multiple levels, impinging on chromatin structure, transcriptional regulation and microRNA maturation, shaping the proteome and the cell's metabolic pathways, and also exerting cytoplasmic functions and displaying cell‐extrinsic effects. These tumorigenic activities are inextricably linked with the blend of highly corrupted processes that characterize the tumor context. Recent studies indicate that successful strategies to extract core aspects of mutant p53 oncogenic potential and to identify unique tumor dependencies entail the superimposition of large‐scale analyses performed in multiple experimental systems, together with a mindful use of animal models. This will hopefully soon lead to the long‐awaited inclusion of mutant p53 as an actionable target of clinical antitumor therapies. Targeting the mutant p53 oncogenic network for cancer therapy. Recent research demonstrates that p53 missense mutant proteins reprogram fundamental cellular pathways with cancer‐promoting outcomes. Detailed knowledge of mutant p53 gain‐of‐function mechanisms discloses specific tumor weaknesses, actionable targets, and molecules for precision therapies.