P53 and TP53: Critical objective in cancer research

Mutation of P53 and TP53

Mutations in the TP53 gene abrogate the tumor suppressor activities of its encoded protein, p53. The TP53 gene is mutated in approximately half of all human malignancies, including those of the breast, colon, lung, liver, prostate, bladder, and skin. Cancer-associated TP53 mutations are predominantly missense mutations, causing single amino acid substitutions. Typically, most cancer-associated mutations fall into one of two categories:

1. DNA contact mutants, in which p53 residues responsible for sequence-specific binding to DNA are altered.
2. conformational or structural mutants, in which the protein becomes extensively misfolded.

Although many hundreds of different p53 mutations have been recorded, some of them are particularly common and are therefore referred to as hotspot mutations. such as R175, G245, R248, R249, R273 and R282, have been so far identified.

Oncogenic function of mutant p53

In contrast to wild-type p53 anti-tumor activity, mutant p53 proteins have oncogenic action in culture cells, and promote metastasis and genomic instability in mice models. Although having lost the ability to interact directly with p53-binding sites within the DNA, mutp53 can still piggyback on other transcription factors to drive tumor-promoting gene transcription. In addition to the cell-autonomous activities, mutp53 can also modulate the tumor microenvironment (TME), rendering it more cancer supportive, respectively. For example, mutp53 can support tumor progression by modulating exosome content in a manner that leads to reprogramming of macrophages to an M2 state, thereby generating a more favorable TME25.

Fig. 2: Tumor-suppressive effects of wild-type p53 and oncogenic effects of mutant p53

Cancer therapy

• Gene therapy

Several studies have shown that transfection of cancer cells with wild-type p53 expressing plasmids can induce apoptosis and/or growth arrest. Several clinical research investigations using viral and non-viral vectors delivering p53 genes, alone or combined with other therapeutic agents, have been completed so far.

• Target therapy

PhiKan083 and PK7088 are small chemicals that bind p53 and generate the Y220C mutant, stabilizing it and boosting the amount of wild-type p53. Other molecules, including PRIMA-1, PRIMAmet/APR-246, CP-31398, and SCH29074, bind to mutant p53 proteins and interact with DNA binding domains to facilitate proper mutant protein folding and p53 function recovery. COTI-2's third-generation thiosemicarbazone, as well as particular peptides, have recently been shown to convert reactive mutant p53 protein to a form with wild-type characteristics. These drugs have been demonstrated to have anticancer action in preclinical models expressing mutant p53. Two of these drugs, APR-246 and COTI-2, have made it to clinical trials so far. In January 2020, the FDA granted breakthrough designation to APR-246 for MDS treatment, and a phase III multicenter randomized trial for the combined treatment was initiated (NCT03745716).

Creative Diagnostics developed a panel of high quality materials targeting p53 to assist our global customers in their research of the functions, oncogenic pathways, and potential treatment of p53 and Tp 53.