Source: The Francis Crick Institute
Summary: According to a new study, the researchers found that the breast cancer drug lapatinib which is designed to shrink tumours can sometimes cause them to grow in the lab.
Around 20% of breast cancers are caused by a massive excess of a protein called HER2 (human epidermal growth factor receptor 2), which sends signals telling cancer cells to grow and divide. Lots of treatments for HER2 positive breast cancer work by switching off HER2 to make the cells stop growing or die. They can do this from outside the cell (antibodies such as trastuzumab) or inside the cell (kinase inhibitors such as lapatinib). Lapatanib is one of many kinase inhibitors used to treat HER2 positive breast cancers and HER2 is an important target for other existing and emerging breast cancer treatments. Lapatinib is used in combination with other cancer drugs and chemotherapy to treat patients with a particular type of advanced breast cancer, but failed clinical trials as a stand-alone treatment. Researchers from the Francis Crick Institute found that the breast cancer drug lapatinib which is designed to shrink tumours can sometimes cause them to grow in the lab. The study findings were published in the journal eLife.
Using a combination of biochemical, biophysical, and computer modelling tools, the team discovered that lapatinib causes HER2 receptors on cell membranes to pair up with a partner receptor called HER3. When you combine these inhibitor-induced HER2-HER3 pairs with naturally-occurring growth signals from outside of the cell, they can rearrange themselves into an active, signalling pair. In this state, the HER2-HER3 pair becomes very efficient at telling the cells to divide, more so than cells that haven’t been treated with the drug. By understanding the molecular basis of this phenomenon, scientists hope that their findings will lead to safer treatment decision-making and drug design in the future.
Dr. Justine Alford from Cancer Research UK, said: “By revealing surprising insight into the biology of HER2 and how this molecule may respond to certain drugs, this important lab research could guide future work into sophisticated new treatments that target HER2 in a more effective way.”
More Information: Jeroen Claus et al, “Inhibitor-induced HER2-HER3 heterodimerisation promotes proliferation through a novel dimer interface”, eLife (2018). DOI: 10.7554/eLife.32271