This is important because these structures are going to respond differently to anti-cancer drugs and have different activation levels. The research lays down a firm foundation for others in translational research to use these findings to design more effective and universal cancer treatment therapies.
The publication titled “The architecture of EGFR's basal complexes reveals autoinhibition mechanisms in dimers and oligomers" looked at the structure of epidermal growth factor receptors (EGFR's) before activation. EGFR's are a family of proteins located on the surface of cells. They become activated by a growth factor molecule binding, this causes an intracellular signal, allowing the cell to respond to the growth factor by changing its gene expression. A common response is the growth and replication of the cell. In the case of some cancerous cells, the EGFR mutates, resulting in over-activation of the EGFR, uncontrolled cellular growth and finally tumour formation.
“We know how the receptor should look like when it is not active and we have a good understanding of which structures it can adopt when it's activated and so now we can look to stop it. The structures reported in this paper relate to cancer signalling, and may be important for resistance to therapeutics. We're able to look at the structure and try and figure out if it has anything to do with why some drugs don't work with mutated receptors." - Dr. Laura Zanetti-Domingues, OCTOPUS.
The OCTOPUS imaging cluster used single particle tracking and FLimP to complete part of the research. The protocols for the techniques were developed at OCTOPUS as well as the analysis pipeline. These techniques are available to users on site and members of the group have started collaborating with industrial partners to improve FLimP as presently it is a difficult and specialised technique; however the partnership aims to make it more user friendly, faster and more automated.
The group looked at the receptor in the wild type state, as you would find it normally, as well as introducing mutations, some scenarios where you could activate/deactivate the receptor. The research team picked mutations relevant to cancer and tested how the basal state (pre-activation state) of these receptors behaved, in order to relate to what happens when they become over-activated and how to prevent this.
This new publication written by M. Martin-Fernandez et al builds on work started up to five years ago. The multinational effort had contributors from the UK, USA, Australia and Holland laying the groundwork for future research, having a meaningful impact in the field of cancer research.
A previous paper published by members of the current research group, looked at the structure of the receptor when it was activated and receiving signals. In the current publication, the focus is on the EGFR's in their primed state, before activation. The presiding theory of 20 years or so, said that the receptors were monomers (meaning isolated by themselves around the cell) and then upon growth factor binding (sending the signal into the cell) the receptors need to be no longer alone. The receptors “glue" together and are then present in pairs or large groups of up to 10 receptors.
The results of this paper show that by using a combination of different microscopy techniques, molecular dynamics simulations and biochemistry, when the receptors are in their primed state, they are not single units. There are different structures which relate to different states of pre-activation.
The full publication is available here.
More information on OCTOPUS can be found here.
The publication is available under Open Access license which can be viewed here.