Researchers at The University of Kansas Cancer Center have found that high doses of drugs commonly used to fight high cholesterol can destroy a rogue protein produced by a damaged gene that is associated with nearly half of all human cancers.

Tomoo Iwakuma, MD, PhD, an associate professor in the Department of Cancer Biology, and his team have published the first research showing how the use of statins can shut down structurally mutated p53 proteins that can accelerate cancer progression, while not harming proteins produced by healthy p53 genes. Although statins are not a cancer treatment per se, the understanding of how they affect mutated forms of p53 could lead to new medications designed specifically to knock out the damaged p53.

The challenge for Iwakuma and his team was to find out how to eliminate the misbehaving protein, while leaving cells containing healthy p53 needed for normal cell growth unharmed.

Four years ago, Iwakuma and his lab team collaborated with the High Throughput Screening Laboratory (HTC) on the University of Kansas Lawrence campus to screen compounds to find out which ones might degrade mutant p53. Of the nearly 9,000 compounds they tested, about 2,400 were Food and Drug Administration (FDA)–approved drugs, while the others were non–FDA approved and uncharacterized compounds.

When Iwakuma got an email from the HTC listing the 10 compounds that the screenings had shown promise in reducing mutant p53 levels, he was shocked to see that some of them were statins.

Early screenings often produce false positives, so Iwakuma had to verify the lab results, first testing them in cells and then in mice. The KU researchers injected the mice with cells expressing mutant p53, waited for tumors to form, and then treated them with high doses of statins for 21 days. They found that tumors did not grow well in mice treated with statins compared to the controls, and they learned the statins worked only on structurally mutated (misfolded) p53, as opposed to p53 mutated at the spot where it binds to DNA. This was an important discovery, particularly since clinical research with statins had not considered the type of p53 mutation.

"We found that only the structural mutation is affected," Iwakuma said. "Which explains why clinical studies with statins were inconclusive."

"Once we knew for sure statins degraded mutant p53, we still had to figure out how," explained Atul Ranjan, PhD, a post–doctoral researcher in cancer biology at KU and co–author on the study. "We needed to find out exactly how the statins work for p53 degradation; which other proteins are involved in the mechanism."

The researchers identified DNAJA1 as a heat shock protein that binds to misfolded mutant p53 and thus protects the mutant p53 from an enzyme that flags damaged or misshapen proteins for destruction.

It turned out that the same mechanisms that help statins reduce cholesterol are at work preventing mutant p53 from binding to DNAJA1, leaving these mutant proteins unprotected. As a result, mutant p53 is free to attach to the enzyme that leads to its degradation. And since mutant p53 is not usually present in normal cells, all this happens without affecting healthy cells.

Going forward, researchers know that many challenges await them, including finding ways to target DNAJA1 directly, now that they know its absence results in mutant p53 being degraded. Iwakuma also sees potential to use statins or another p53–degrading drug in conjunction with chemotherapy.