New approach examines how medicines act on cells

Researchers from the Harry Perkins Institute of Medical Research and The University of Western Australia have developed a new approach to monitor how medicines interact with and modify the activity of living cells. The approach could be relevant for cancer research.

Using CRISPR/Cas9, the researchers attached a super-bright glowing molecule, derived from deep sea shrimp, to specific molecules important for signalling in cancer cells, ‘receptors’. Receptors are molecules that receive signals from outside of the cell and tell the cell how to respond.

Using live cells and a technique that detects when the glowing molecules come into very close proximity, the researchers were able to observe how signalling molecules called chemokines influence the functioning of naturally occurring receptors.

“Existing methods to look at these kinds of events within a cell often require large amounts of the receptor to be forced into a cell, much more than would normally be found in there. Filling a cell up with receptor protein like that can disrupt the normal balance of proteins, which changes how cells work. This is an issue as normally cells only have very small amounts of these receptors. Our new method allows us to monitor receptors at levels that are normally found in cells,” said Dr Carl White, who led the research with Associate Professor Kevin Pfleger.

The receptors that are the major focus of this study are well known to play a role in cancer, but exactly how is still not clear. Beyond cancer, the methodology is applicable to a multitude of conditions, from cardiovascular disease and diabetes, through to neurological disorders.

“Because we are observing effects on proteins at the levels they exist at normally in the cells, we can use this new methodology to better understand how diseases change the way these receptor proteins function and pinpoint the best way of targeting them,” Dr White said.

“Currently many treatments that work in preclinical models don’t work in clinical trials. It is therefore crucial in the preclinical studies to use methods that better represent the true cellular environment.”

Associate Professor Pfleger, who is also the chief scientific advisor of Dimerix Limited, highlighted that “This work has considerable potential for improving drug discovery processes, including leveraging both Dimerix’s Receptor-HIT platform developed at the Perkins, and the latest advances in genome editing.”

The study was published in the journal Scientific Reports. The work was funded by National Health and Medical Research Council fellowships to Dr White and Associate Professor Pfleger, as well as Linkage Grants from the Australian Research Council in partnership with Promega, BMG Labtech and Dimerix.