Genetically manipulating and removing the most common mutant form of the p53 gene that promotes colorectal cancer in humans reduces tumor growth and tissue invasion, according to new research.
Specific “hotspot” mutations of p53 have recently been recognized as strong promoters of cancer in humans. About 60 percent of colorectal cancers harbor p53 mutations. The challenge for scientists has been discovering whether and which mutant forms of p53 are best to target—and in which tumor entity—in order to halt the cancer process or slow it down.
In this study, Moll and colleagues assessed one of the three most common p53 mutants in colorectal cancer—mutp53 R248Q, exchanging an Arginine (R) for a Glutamine (Q)—in a high fidelity genetic mouse model of the disease.
The researchers found that therapeutically ablating the mutant p53 gene in mice that had developed colorectal cancer markedly inhibited tumor growth and reduced tumor invasiveness by 50 percent.
As an underlying mechanism, they identified that the mutant p53 protein (produced from its corresponding gene), which is highly stabilized in the tumor cells, binds to and activates Stat3, a key tumor promoter. This promotes cancer progression and correlates with poor outcomes in humans and mice.
The researchers demonstrated that Stat3 activation via the mutant p53 protein mediates tumor growth and invasion. They also showed that many human cancer entities including gastrointestinal cancers with R248 mutations are associated with poorer patient survival compared to those with nonR248 mutations of p53.
Moreover, the researchers found that genetic deletion of mutant p53 was only one way to slow down tumor growth and progression.
The researchers also discovered that by inhibiting the folding chaperone enzyme Hsp90—which they discovered earlier to be responsible for mutant p53 protein stabilization—with a small molecule drug called 17AAG, they could equally stop Stat3 signaling, tumor growth, and progression of mutp53-driven tumors.
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“We discovered that in p53-mediated colorectal cancer driven by the most common mutant form of p53, there is an exploitable tumor dependence on continued expression of the mutant protein for the tumors to thrive,” says Moll.
“Our data suggest that this and similar p53 mutants represent actionable drug targets responsive to treatment by removal, for example with Hsp90 inhibitors,” she summarizes.
Additional coauthors of the paper are from the University Medical Center in Göttingen, Germany. The National Cancer Institute and the German National Science Foundation supported this research.
Source: Stony Brook University
