Targeting mutant p53 in cancer: a long road to precision therapy.
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.
Laboratorio Nazionale CIB (LNCIB), Trieste, Italy.|Dipartimento di Scienze della Vita, Università degli Studi di Trieste, Italy.
Fiamma
F
Mantovani
Laboratorio Nazionale CIB (LNCIB), Trieste, Italy.
Dawid
D
Walerych
Laboratorio Nazionale CIB (LNCIB), Trieste, Italy.|Dipartimento di Scienze della Vita, Università degli Studi di Trieste, Italy.
Giannino Del
GD
Sal
D000818:Animals; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D058990:Molecular Targeted Therapy; D050505:Mutant Proteins / Q000235:genetics* / Q000627:therapeutic use; D009369:Neoplasms / Q000235:genetics* / Q000628:therapy; D057285:Precision Medicine; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000627:therapeutic use
D035683:MicroRNAs; D050505:Mutant Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
gain-of-function; missense mutant p53; oncogenic signaling; precision therapy; tumor environment