Targeted cancer therapies – drugs that interfere with specific molecules to block cancer growth and spread – have revolutionised the treatment of certain types of tumour. But tumour cells can become resistant to these therapies, and so patients no longer respond to the drugs.
Herceptin binding to HER2 receptors on breast cancer cells
HER2 is a protein important for cell survival found on the surface of cells. Epithelial cells – cells which pack close together in protective or secreting tissues like the lung, intestine and breast – can produce HER2 to control normal tissue function. But HER2 is made at abnormally high levels (called HER2 positive) in cancer cells of around a quarter of patients with breast cancer (and other cancers too). This protein difference in some cancer cells has enabled the creation of drugs that specifically target HER2, such as the small-molecule inhibitor lapatinib and the monoclonal antibodies pertuzumab and trastuzumab. The image above represents HER2 molecules (in grey) on the surface of cancer cells binding to fragments of trastuzumab (also known as Herceptin) (in orange).1 Binding of the drug stops HER2 sticking to itself, which interferes with the over-active survival signals from HER2 and makes the cancer cells stop growing and die.
Unfortunately, patients can develop resistance to HER2-targeted therapies and the drugs no longer work as they should. This is a major clinical problem, so new approaches to overcome it are urgently needed.
Last year, Val Brunton gave a talk at the Biochemical Society Focused Meeting on Signalling and Acquired Resistance to Targeted Cancer Therapeutics about our efforts to begin to characterise how drug resistance develops in HER2-positive breast cancer. As well as using lapatinib, we have begun to explore sapatinib, an anti-HER2 drug developed by AstraZeneca, to understand the proteins that change when cancer cells become drug resistant.
Understanding the significance of other protein changes in cancer cells resistant to anti-HER2 therapies could enable us to target these proteins to treat drug-resistant tumours. This will have a considerable impact on the treatment of patients with HER2-positive breast cancer in the future.
A paper associated with Val’s talk summarises our work so far and places it in the context of other molecules and, more broadly, breast cancer patients so that we can move to try to translate this and other new research into clinical benefit.
Note
1For the image, I rendered the HER2 receptors and drug fragments using the crystal structure of the extracellular portion of HER2 bound to a Herceptin Fab fragment (PDB code 1N8Z) as a template. (The full Herceptin antibody would be about three times larger than the orange Fab fragments shown.)
Funding
This work was supported by Cancer Research UK and AstraZeneca.
Citation
Creedon et al. Exploring mechanisms of acquired resistance to HER2 (human epidermal growth factor receptor 2)-targeted therapies in breast cancer. Biochem. Soc. Trans. 42, 822–830 (2014)
Adam Byron 
[…] Up to about a quarter of breast cancers are HER2 positive. These cancers tend to grow more quickly and spread more aggressively than other breast cancers. However, therapies targeted at HER2 (often given in combination with chemotherapy) can be used to treat HER2-positive breast cancer (see a previous post). […]