The tumor-suppressor protein p53 acts as a crucial ‘brake’ against unrestrained cell division, and many cancers arise from mutations that disrupt p53 function. Most chemotherapeutic strategies work by preferentially targeting these actively dividing cells, but such approaches inevitably end up wiping out a certain percentage of healthy bystanders as well, creating toxicity issues for patients.
A multi-drug strategy developed recently by David Lane’s team at the A*STAR p53 Laboratory in Singapore now promises to greatly reduce such collateral damage. “We were trying to establish different approaches and methodology that will kill p53 mutant cells selectively,” explains Chit Fang Cheok, a postdoctoral researcher with Lane’s group.
Cheok and her co-workers focused their study on VX-680, an ‘aurora kinase inhibitor’ drug that interferes with the replication and redistribution of genetic material during mitosis, yielding cells that contain an inappropriate number of chromosomes and subsequently undergo cell death. Although p53 expression was previously believed to act as a safeguard against VX-680 toxicity, the researchers found that every cell line they tested was affected by the drug to some extent, regardless of the presence or absence of functional p53.
The team found, however, that they could constrain the effects of VX-680 with nutlin-3, a recently identified molecule that temporarily arrests division of cells expressing functional p53. Pre-treatment with nutlin-3 proved to be sufficient to protect such cells against both the chromosomal replication abnormalities and cell death associated with exposure to VX-680, without any apparent negative effects. A mixed population of p53-expressing and -deficient cells was subjected to this two-stage treatment, and after five days the resulting culture consisted overwhelmingly of cells with wild-type p53 (Fig. 1). “This suggests to us that such a combinational therapy may be useful in targeting p53-mutant tumors in patients,” says Cheok.
Other studies have shown that nutlin-3 treatment is tolerated by immunodeficient mice, indicating that it could be safe for use in a clinical setting, and Cheok anticipates that this drug could be paired with a number of other chemotherapeutic agents. “Potentially, any drug that [targets] cell division to achieve killing will be useful in combination with nutlin-3,” she says. “However, this will require empirical testing to assess toxicity of the drug combination versus efficacy in selective killing of p53-mutant tumor cells.” To this end, she and the other members of the Lane group are now focused on moving their approach from the culture dish to live animals, as a prelude to potential future clinical investigations.