Some potential cancer therapies may do more harm than good: A class of compounds intended to boost tumor suppressor p53 activity may actually promote mutant versions of the gene, a
study published tomorrow in
Genes and Development reports.
p53, the tumor suppressor found in roughly half of all human cancers, works by signaling cell death, thus keeping cell growth in check. But p53 can be deleted during transcription or mutated by missense mutations. When mutated, it expresses deleterious proteins that spur tumorigenesis, and researchers have assumed these mutations are stable. If deleterious proteins in the tumor aren't detectable, researchers generally conclude that the p53 gene has been deleted.
The new study, led by
Guillermina Lozano, from MD Anderson Cancer Center, shows that this assumption is incorrect. The researchers used knockin mice to demonstrate that in some cases, missense mutations in p53 can indeed produce harmful proteins, but in other cases -- when it's unstable -- it does not.
Lozano's group also extended their findings to the activity of a p53 inhibitor called Mdm2, the target for two drugs researchers are hoping to move into clinical trials. In normal cells, Mdm2 downregulates p53 to prevent premature cell death; the novel drugs disrupt the relationship between p53 and Mdm2 in order to
boost p53 activity, blocking tumorigenesis. However, this study suggests that in cases where p53 is mutated, the drugs simply stabilize the mutated gene, thereby prompting the expression of deleterious proteins.
"I think there will be a lot of skepticism" toward this study, Lozano told
The Scientist. "It's going against dogma: The field thinks p53 mutant automatically is stable" and produces metastasis.
"p53 mutational status in tumors may dictate the response to therapy in more ways than previously realized," Eileen White, from Rutgers University, and Carol Prives, from Columbia, wrote in an accompanying analysis in
Genes and Development. They added that researchers need to determine whether tumor p53 is mutated or not in order to determine if drugs that disrupt the Mdm2/p53 relationship will be beneficial.