Recent Study by CSI Researchers Holds Promise for Improved Therapeutic Treatment of Tumours with Mutated p53

Tumours with missense mutant p53 (mutp53) acquire additional oncogenic gain-of-function (GOF) based on their unique structural modifications. These GOF DNA binding domain (DBD) mutations lose their tumour-suppressive ability, yet favour cancer cell proliferation, migration, metastases as well as rendering resistant to chemotherapies.

In this interesting study, researchers from CSI Singapore delved into the oncogenic GOF mechanisms of p53 codon 158 (Arg158) mutation, a recurrent point mutation that is under-researched compared to other mutp53 hotspots. Helmed by Prof. Goh Boon Cher and Dr. Kong Li Ren, the experimental therapeutics team first demonstrated that the mutation could lead to oncogenic GOF, but through a distinct mechanism from other hotspots which have been shown to perturb DNA binding and result in transcription of chromatin regulatory genes. The Arg158 mutation results in exquisite sensitivity to acetylation of p53, altering its DNA binding spectrum and upregulating TRAIP, a RING domain-containing E3 ubiquitin ligase.

The group observed a connection between TRAIP and Nuclear Factor Kappa-B (NF-kB) signalling, a pathway commonly associated with inflammation and gene expression in tumour cells. The increase in TRAIP as a result of mut53 acetylation disrupts NF-kB pathway signalling, thus sensitising cancer cells to DNA damaging agents such as cisplatin and leading to apoptosis. Through high-throughput compound screening, the team further demonstrated that the acetylation of p53 can be achieved with pharmacologic agents, providing a cogent basis for further clinical development.

Moving forward, the research team hopes to translate their research findings in a clinical trial evaluating active agents in patients harbouring the mutation in their tumours.

Read more about their study here!