'Panic button' could help cancer defy drugs

Stressed yeast cells frantically reshuffle their chromosomes in a desperate last bid to find a combination that survives. This "panic" response enables them to rapidly evolve resistance to drugs.

The discovery might also apply to cancer, because cancer cells often have abnormal numbers and arrangements of chromosomes. Understanding one of the mechanisms by which cancers develop resistance to drugs could in turn open up new ways to combat cancer.

The key panic button driving the reshuffling is heat-shock protein 90 (Hsp90), which normally ensures that chromosomes are faithfully copied when cells divide and multiply. When Hsp90 is knocked out, the chromosomes get completely reshuffled. That's normally a disaster, but in a desperate situation it's a potential lifeline.

Freak cells

A team led by Rong Li of the Stowers Institute for Medical Research in Kansas City, Missouri, exposed baker's yeast cells (Saccharomyces cerevisiae) to stressful stimuli like heat and chemicals, and looked for changes in chromosome replication. The biggest effect came when Hsp90 was disrupted.

The stressed yeast cells lost or duplicated random chromosomes when they divided, producing colonies with a vast array of freak cells. Li then exposed these freak strains to drugs, creating colonies of drug-resistant yeast.

Unique chromosome shuffling patterns evolved in the different yeast cells, helping some of them survive the various drugs. For instance, in four of the five colonies that survived a dose of fluconazole, each yeast had an extra copy of chromosome 8. This carries the ERG11 gene, which can make organisms resistant to fluconazole. By having twice the usual number of ERG11 genes, the shuffled yeast survived the onslaught.

Shuffled cancer?

We don't know if human cancer cells that lack Hsp90 also change their chromosomes. Li points out that, unlike yeast cells, human and mammalian cells have a protein called p53 that kills cells with abnormal numbers of chromosomes. But in half of all cancers, p53 malfunctions, which means that if cancers with shuffled chromosomes do exist, they could survive and evolve drug resistance.

Li says her discoveries offer a new insight into how to treat cancer. "We may need to understand not only what a cancer is currently, but also how it will evolve in response to treatment," says Li. "If we can predict cancer's evolutionary path, we may have a better chance to corner it."

"The next step is to understand whether this shuffling is predictable and controllable," she says.

"Unstable chromosomes have been associated with cancer cell resistance to a number of drugs," says Rebecca Burrell of Cancer Research UK's London Research Institute.

Paradoxically, some drugs that disable Hsp90 have shown promise against cancer, by stopping the cancer from building proteins it needs to survive. "If our findings hold true in human cells, [these drugs] may be counterproductive," says Li. "Hsp90 inhibitors might actually help cancer cells evolve drug resistance."

"If these data can be replicated in cells from more advanced organisms, they may begin to raise concerns about targeting Hsp90 in the clinic because of the potential to cause diversity in tumour cells," Burrell agrees.

Journal reference: Nature, DOI: 10.1038/nature10795

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