Thwarting cancer by targeting cell survival and growth

Breast Cancer Cells
University of Toronto scientists found they could slow down the proliferation of breast cancer cells by inhibiting a protein called NUAK2. (National Cancer Institute)

Some cancer cells initially respond well to drug treatments, but then become resistant and start growing again. Others simply grow so fast that drug treatments can’t keep up with them. Two studies out this week suggest potential methods for treating hard-to-beat tumors by targeting the mechanisms by which they survive and proliferate.

The first, published in the journal Cell Reports, focuses on a mechanism known as “autophagy,” which is like a recycling system inside cells. When cells undergo autophagy, they deliver waste products to components inside the cell called lysosomes, which contain enzymes that digest and break down the material. This becomes an energy source.

Researchers from the University of Cincinnati in Ohio discovered that part of the energy center of cells, mitochondrial complex I, can both increase autophagy and control its duration. Genetic abnormalities in this complex prevent the autophagy that’s triggered by a class of cancer drugs called mTOR inhibitors.

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They also found it’s possible to increase autophagy by changing the metabolism of mitochondria. "Our data demonstrate the importance of metabolism in the regulation of autophagy, increase our understanding of clinically relevant drugs that are important for cancer, and suggest new strategies to increase or inhibit autophagy," said co-author Carol Mercer, an associate professor in the division of hematology and oncology at the university, in a statement.

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Researchers at the University of Toronto zeroed in on a protein called NUAK2 that’s produced by cancer cells. The gene that produces NUAK2 is switched on by two known cancer-promoting proteins, YAP and TAZ, which bolster abnormal cell growth, the team discovered.

The team showed that if they blocked NUAK2 either with a drug or by mutating the gene, they could slow the growth of breast cancer cells and breast tumors in mouse models. They published the discovery in the journal Nature Communications.

The researchers believe patients’ tumors could be tested for high levels of NUAK2, which could be targeted with a drug similar to the one they used.

"We looked at bladder cancer and found that a subset of patients have high levels of NUAK2 protein in their tumors which also happened to be high-grade tumors," said lead author Liliana Attisano, professor at the University of Toronto, in a statement. The team is now working on turning the compound they developed into a drug they can take into animal studies.