In many very invasive forms of breast cancer, the cells have too much of the receptor HER2 on their surface. This leads to uncontrolled growth of the cells. Various antibodies such as trastuzumab and pertuzumab, which recognize the HER2 receptor, have been used in breast cancer therapy for many years now. However, these antibodies do not kill off the cancer cells. Instead, they render them dormant, and the cancer cells can become active again at any time.
A team at the University of Zurich has now found out why these antibodies merely slow tumor growth rather than killing off the cancer cells. The receptor HER2 uses several signaling pathways at the same time to inform the cell that it should grow and divide. But the antibodies available thus far only block one of those signaling pathways, while the others remain active.
Authors show an adaptation mechanism leading to reactivation of the PI3K/AKT pathway during trastuzumab treatment, which occurs independently of ErbB3 re-phosphorylation. This signalling bypass of phospho-ErbB3 operates in ErbB2-overexpressing cells via RAS-PI3K crosstalk and is attributable to active ErbB2 homodimers. As demonstrated by dual blockade of ErbB2/RAS and ErbB3 by means of pharmacological inhibition, RNA interference or by specific protein binders obstructing the RAS–p110α interaction, both routes must be blocked to prevent reactivation of the PI3K/AKT pathway.
The most important of these open paths leads through the central hub called RAS. "It is this protein that is responsible for reactivating the growth signal emitted by the HER2 receptor. The antibodies lose effect and the cancer cells continue to proliferate". This is how senior author explains the mechanism, which has been understood in detail for the first time.
The UZH scientists have now discovered an astonishingly effective solution to switch off all signals emanating from HER2 in the cancer cells at the same time. They have designed a protein compound that binds itself 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 interior, and the cancer cells die off. Another advantage is the very selective effect of the substance, which ensures that the cancer cells are killed off efficiently but healthy body cells remain unharmed. For example, the innovative protein substance has caused the tumors in mice to regress without endangering the health of the animals.
The active ingredient comprises several DARPins (designed ankyrin repeat proteins). This new class of protein compounds that are easy to produce and have a large number of favorable binding properties. DARPins trapping ErbB2 in a dimerization-incompetent state, which entail pan-ErbB inhibition and a permanent OFF state in the oncogenic signalling, thereby triggering extensive apoptosis in ErbB2-addicted tumors.
Promising treatment prospects for invasive breast cancer
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