Scientists at the University of Zurich in Switzerland have been able to understand for the first time why many cancer cells quickly adapt to treatment with therapeutic antibodies in invasive forms of breast cancer. Instead of dying off, they are merely rendered inactive. The researchers have developed an active protein compound that kills cancer cells without harming healthy cells.
In many invasive forms of breast cancer, the cells have too many human epidermal growth factor receptor 2 (HER2) receptors on their surfaces, which leads to uncontrolled cell growth. Various antibodies, such as trastuzumab and pertuzumab, which recognize HER2 receptors, have been used in breast cancer therapy for many years. These antibodies, however, do not kill cancer cells but only render them dormant, and the cells can become active again at any time.
The Swiss team has discovered why antibodies merely slow tumor growth rather than killing off the cancer cells. The HER2 receptor uses several signaling pathways at the same time to inform the cell that it should grow and divide. The currently available antibodies block only one of those signaling pathways, while the others remain active. The most important of these open pathways leads through a central hub called RAS.
“It is this protein that is responsible for reactivating the growth signal emitted by the HER2 receptor,” explained lead investigator Dr. Andreas Plückthun. “The antibodies lose effect, and the cancer cells continue to proliferate.”
The scientists have come up with a way to switch off all of the signals emanating from HER2 receptors in cancer cells at the same time. They have designed an active protein compound that binds simultaneously to two HER2 receptors in a targeted manner and changes their spatial structure. This “receptor bending” prevents any growth signals from being transmitted into the cell’s interior, and the cancer cells die off. The protein compound has a very selective effect, which ensures that cancer cells are killed off efficiently while healthy cells remain unharmed, according to the researchers.
The active ingredient comprises several DARPins (designed ankyrin repeat proteins). The researchers’ aim is to test the first drug with this new mechanism of action in human subjects as soon as possible. Plückthun is optimistic: “Now that we have identified the Achilles heel of HER2-positive cancer cells, new opportunities are opening up for treating invasive tumor types like breast cancer more effectively in the future.”
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