Posted by: Sophie Khatib27 JAN 2013
HER2 is a protein which is found on the surface of some cancer cells and is linked with breast cancer. Some people with breast cancer over express HER2 and in these cases, the tumour is said to be HER2 positive. HER2 positive breast cancers have been shown to grow quicker than other types of breast cancer and therefore have a higher rate of metastasis and mortality.
The discovery of these HER2 overexpressing cells lead to the development of trastuzumab, an antibody which stops a growth factor binding to HER2 and stimulating its growth.
Lapatinib is a relatively new drug and is an inhibitor of both HER2 and EGFR, epidermal growth factor receptor. Lapatinib is recommended when patients with HER2 positive breast cancer have not responded to trastuzumab. In these trastuzumab unresponsive patients, it is thought that the PI3K/mTOR pathway is dysregulated. 4E-BP1, an mRNA translation repressor, is a downstream target of mTOR, and when this was knocked out in a cell line, they became more sensitive to mTOR, possibly showing that an overstimulation of 4E-BP1, or one of its targets, is linked to resistance to trastuzumab and possibly even to lapatinib. This may even be linked to a survival gene which is activated when an environment is under stress, such as the introduction of a chemotherapeutic agent. It is also interesting to note that mTOR inhibition, for example administering temsirolimus, in addition to lapatinib reduces resistance of the cells, thereby pharmacologically mimicking the knockout 4E-BP1 cells. The co-administration of an mTOR inhibitor alongside lapatinib shows synergistic activity and is potentially an extremely useful combination, especially in those patients who test HER2 positive but are unresponsive to trastuzumab.
Clinical trials are currently underway, many recruiting patients who have been unresponsive to trastuzumab but test HER2 positive when the tumour is biopsied. These studies are currently testing the combination of everolimus, another mTOR inhibitor, with lapatinib in triple negative or locally advanced breast cancers but they are in the extremely early stages of the trial, many still recruiting.
Does this then mean that there are different pathologies in play when a patient’s tumour expresses high levels of HER2. If there was only a single pathway that is activated by the overexpression of HER2, all patients would be expected to respond to trastuzumab but since some are still resistant, are survival genes being switched on and alternative pathways activated? Or is it simply that in some patients, the drug is not getting to the desired site of action? It will be interesting to follow these studies and assess the outcomes of co-administration of other drugs to see if this resistance can be overcome. I think it will tell us an awful lot about the physiology of HER2 positive cancers and may even lead to the development of new drugs that could work in all cases. But until then, we have to make do with the best we have. If these trials do prove that this new drug combination is effective, all patients could be tested for the expression of mTOR at the same time as testing for HER2. Since HER2 testing has become routine in all patients with newly diagnosed breast cancer, it would not be that much of a leap to suggest that we then also test for mTOR expression to specifically select those patients likely to be unresponsive to trastuzumab and start them on the correct therapy straight away. After all, if we have the right drugs and tests available, why should we not be utilising them to the best of their ability?!
We are now looking at a time when instead of just looking at a receptor and developing a drug to target that receptor, we need to understand the pathway and the complex role that each part in that pathway plays. It is only then, that we can understand what will be affected after pharmacological intervention and any potential problems with this. It the new world of pharmacy and drug development and it really REALLY interests me!