No matter what type of chemotherapy you attack a tumour with, many cancer cells resort to the same survival tactic: They start eating themselves.
A team of scientists at Brigham Young University have uncovered two essential proteins that bind to one another triggering this mechanism of autophagy1.
Understanding the mechanisms involved in cancer cell survival opens the door to the development of therapies which could help target this, blocking autophagy in tumours and ultimately making them more sensitive to chemotherapy treatments. This may allow for the use of lower chemotherapy doses to treat patients, which could give rise to reduced side effects.
With the possibility of improved quality of life for many cancer patients, the hunt for this molecular switch has been carried out across numerous labs internationally. ATG9 is a protein that has been highly implicated in the control of autophagy in response to stress, and numerous labs set out to identify its binding partner among the many thousands of proteins in a cell. However, the research of the BYU team, composed mainly of undergraduates, set out to answer a different question- they were interested in why cancer cells seemingly produced a surplus of the regulatory protein 14-3-3?- and in doing so stumbled upon ATG9 as a binding partner and the autophagy molecular switch.
The BYU team used breast cancer tissue as a model and forced the tumour cells to undergo autophagy by depriving them of both oxygen and glucose. Comparison of the stress-induced cells with controls demonstrated that the interaction between ATG9 and 14-3-3? only occurred under hypoxic conditions. Under these conditions 14-3-3? undergoes a dynamic rearrangement of its interactome and ATG9 is phosphorylated, allowing the two proteins to interact. This interaction switches the cancer cells to survival mode. By targeting this interaction to prevent the cancer cell’s inherent survival mechanism chemotherapy could be even more effective.
Several medicines do apparently already exist that could be used to block autophagy and improve the efficacy of chemotherapy. One such compound is the anti-malarial drug chloroquine, but if this proves ineffective or unsafe for use in cancer patients, the findings of Andersen’s team at BYU have highlighted the target to allow the development of a new drug specific to the task.
Affimer technology, developed by Avacta Life Sciences is an engineered antibody alternative that can be targeted to bind proteins in their different native states and have been designed to act as an antibody alternative in many traditional affinity applications without any change to the workflow.