Abstract
The transcription factor p53 is a key tumor suppressor that is inactivated in almost all cancers due to either point mutations in the TP53 gene or overexpression of its negative regulators. The p53 protein is known as the “cellular gatekeeper” for its roles in facilitating DNA repair, cell cycle arrest or apoptosis upon DNA damage. Most p53 mutations are missense and result in either structural destabilization of the protein, causing its partial unfolding and deactivation under physiological conditions, or impairment of its DNA-binding properties. Tumor cells with p53 mutations are generally more immunogenic due to “hot spot” neoantigens that instigate the immune system response. In this review, we discuss the key therapeutic strategies targeting mutant p53 tumors, including classical approaches based on small molecule intervention and emerging technologies such as gene editing and T cell immunotherapy.
Highlights
The transcription factor p53 functions as a tumor suppressor and is considered as one of the most promising molecular targets for cancer therapy, as it regulates a plethora of intracellular metabolic pathways, including DNA damage repair, apoptosis, and senescence
The p53 protein is widely known as the “guardian of the genome” that prevents the proliferation of cells harboring genetic aberrations, notably oncogenic mutations
The loss of transcriptional functions leading to the deactivation of intrinsic tumor suppressive responses associated with wild-type (WT) p53 is the primary outcome of p53 mutations, and is a hallmark of most cancers The majority of p53 mutations are missense, i.e., cause single residue substitutions, and occur within the DNA-binding domain (DBD)
Summary
The transcription factor p53 functions as a tumor suppressor and is considered as one of the most promising molecular targets for cancer therapy, as it regulates a plethora of intracellular metabolic pathways, including DNA damage repair, apoptosis, and senescence. PRIMA-1 and its methyl analog APR-246 (PRIMA-1MET) are promising small molecules that can restore activity of mutant p53 by interacting with the DNA binding domain, promoting proper folding/function [29] This leads to enhanced expression of pro-apoptotic genes Puma, Noxa, and Bax in p53 mutant cells in addition to activation of cell-cycle genes and PARP cleavage independent of p53 mutation status, as observed in multiple studies that involved various types of cancer such as breast, thyroid, myeloma [30]. The correlation between in vitro thermal stabilization and selective viability reduction in Y220C cell lines represents an important milestone toward first-in-class anticancer drugs that rescue p53-Y220C function This provides a compelling rationale for future lead optimization efforts toward potent, non-toxic targeted agents for reactivating the Y220C mutant in anticancer therapy. The 3rd-generation thiosemicarbazone COTI2 functions through both p53-mediated pathways and p53-independent redox homeostatic mechanisms [43] and has entered a Phase II clinical trial (NCT02433626), it is of note that thiosemicarbazone cancer drug candidates have known nonspecific cytotoxicity and effects on iron metabolic pathways [44]
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