Engineered DNA PROTAC Shows Promise for p53-R175H Mutant Cancers

A synthetic bicomponent compound specifically targets and eliminates a mutant protein associated with multiple forms of cancer. One important mechanism involved in inhibiting the growth of tumors is the tumor protein P53 (TP53). Mutations affecting the TP53 gene can be extremely harmful, impairing the body's capacity to combat tumors and potentially promoting their growth.

Since these are the most prevalent mutations found in cancers, TP53 has long been a promising target for treatment. Nevertheless, the inability to bind to the mutant protein has complicated efforts to destroy it.

Recently, a group of scientists from Xi'an Jiaotong-Liverpool University (XJTLU) and other Chinese research institutions published a study in which they created a brief synthetic DNA sequence that is specifically targeted to a specific mutant form of TP53. This mutation, known as p53-R175H, has been connected to colorectal, breast, and lung cancers. Tumors with this mutation are more likely to develop resistance to cisplatin and other chemotherapy treatments.

Proteolysis-targeting chimeras (PROTACs), such as the novel molecule dp53m, are made up of two parts that cooperate to recognize and break down a target protein. The first part of dp53m does not interact with the non-mutant form of TP53; instead, it binds exclusively to the mutant p53-R175H protein. The second part breaks down the target mutated protein by activating an enzyme known as ubiquitin ligase.

The magic of PROTACs lies in their ability to recruit enzymes to the target protein, which then starts the process of breaking it down.”

Dr. Sijin Wu, Wisdom Lake Academy of Pharmacy, Xi'an Jiaotong-Liverpool University

Potential Treatment

Dr. Wu and co-authors report the outcomes of laboratory tests utilizing dp53m against lung cancer cell cultures and in cancer-stricken mice in their study, which was published in Science Bulletin. The molecule had no effect on cancer cells with other p53 mutations or unmutated TP53, but it inhibited the growth of cancer cells with the p53-R175H mutation.

The tumor growth was significantly reduced in mice treated with dp53m compared to mice that received a saline injection as a control. Additionally, the mice did not gain weight, and all other organs were in good condition, indicating that the molecule is not harmful to healthy cells. Additionally, the study discovered that dp53m treatment enhanced the sensitivity of cisplatin, a chemotherapy agent, to mutant cancer cells.

The development of dp53m provides strong evidence for the feasibility of using short sequences of RNA or DNA as warheads for PROTACs. It also could lead to a new potential therapeutic strategy for diseases associated with the p53-R175H mutation.”

Dr. Sijin Wu, Wisdom Lake Academy of Pharmacy, Xi'an Jiaotong-Liverpool University