Research Lead
Scientists at the Babraham Institute in Cambridge, UK, studying the mechanisms underpinning the development of drug-resistant cancers have identified a target that may pave the way for new therapies.
Their discovery centres on the significance of DNA damage for both normal and cancer cells. A signalling pathway that normally ensures damaged cells are diverted towards cellular suicide, or apoptosis, is blocked in certain cancers, rendering the cells resistant to certain types of treatment.
When DNA damage occurs cells normally trigger a repair response. If the damage is not repaired, the cell is targeted for apoptosis. In normal circumstances this process protects the body from cells that might become cancerous. The cells that do become cancerous by-pass the apoptosis mechanism and survive, despite being damaged.
The Babraham researchers found that DNA damage in normal cells increases the activity of a proton pump located in the cell membrane, known as NHE-1. This raises the pH of the cell and has a critical effect on a protein called Bcl-xL, which has the ability to suppress cell death. In more alkaline environments Bcl-xL is converted into a form that allows cells with damaged DNA to die. The researchers found that this pathway is inhibited in certain cancer cells, thereby inhibiting the mechanism of apoptosis.
Particular kinases are responsible for blocking the effects of Bcl-xL. “This discovery provides new insights into how oncogenes, […] allow cells to accumulate more and more damage to their DNA without dying,” says one of the researchers Denis Alexander. “This new understanding of how oncogenes work also opens up some interesting ideas for future cancer therapies.”
The therapeutic interest in this research comes from the finding that changing pH can switch the Bcl-xL pathway that causes apoptosis back on.
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