Did you know that elephants rarely get cancer? In 2015, their secret was revealed: elephants have 20 copies of a gene called p53, which codes for a protein also called p53 that suppresses tumor growth. Humans, on the other hand, carry only a single copy of the p53 gene compared to the elephants’ whopping 20.
Given that mutations in the p53 protein are responsible for an estimated half of human cancers, there has been an intense search for treatments targeting p53 mutants, either by reactivating their tumor-suppressive function or direct inhibition of oncogenic p53 signaling. However, therapeutic compounds against p53 mutants have either been too toxic or failed to perform clinically.
Hope may be on the horizon, thanks to an international effort involving A*STAR’s Bioinformatics Institute (BII), p53 Laboratory, Institute of Molecular and Cell Biology (IMCB), and the Genome Institute of Singapore (GIS), led by Boon Cher Goh of the Cancer Science Institute, Singapore. In this study, the researchers discovered a previously under-studied mutation of p53 that could be exploited as a potential therapeutic target.
“We noticed that an arginine mutation in codon 158 of the p53 gene is especially prevalent in lung cancers, particularly in squamous cell carcinoma and adenocarcinoma, and that it causes cancer through a mechanism distinct from other mutation hotspots,” said study co-author Chandra Verma, a Senior Principal Investigator at BII.
This mutation, a single nucleotide substitution in codon 158 of the p53 gene that codes for glycine instead of arginine (Arg158), renders the mutant p53 protein defective in DNA binding and no longer able to exert its tumor-suppressive function. Instead, tumors expressing this mutant are found to be more aggressive.
However, the battle is not lost, thanks to a unique phenotype linked to this same mutation. “At the same time, the Arg158 mutation makes p53 exquisitely sensitive to acetylation, exposing an opportunity for targeted treatments,” said study first author Li Ren Kong, a Research Fellow at the Cancer Science Institute of Singapore.
Verma explained that acetylating p53 with the Arg158 mutation alters the protein’s DNA binding spectrum, which results in the upregulation of a protein that makes cancer cells more vulnerable to DNA-damaging agents such as cisplatin. Importantly, this acetylation does not seem to affect healthy cells with the wild-type p53 protein.
To exploit this therapeutic vulnerability, the research team carried out a high-throughput screen for DNA-damaging agents and acetylating compounds that can selectively acetylate Arg158 mutants. They identified several pharmacologic agents that may provide an avenue for further clinical development.
With the help of virtual screens being carried out by Srinivasaraghavan Kannan at BII, Verma and colleagues are now looking for novel p53 acetylators that are more specific for Arg158 tumors and less cytotoxic. In addition, the team has initiated a screening process at Singapore’s National University Cancer Institute, Singapore to identify the prevalence of this mutation in local patient cohorts.
“We believe that a combination of DNA-damaging agents, which is the standard of care for lung cancers, with p53 acetylators will provide promising clinical outcomes for this group of patients,” said Kong.
The A*STAR-affiliated researchers contributing to this research are from the Genome Institute of Singapore (GIS), Bioinformatics Institute (BII), p53 Laboratory, and the Institute of Molecular and Cell Biology (IMCB).