Ras - The engine of Cancer

Hi All

I decided to write a fun article about my project. Hope you like it.

 

7am! Start of the morning rush hour. We’ve all been there; flight delays, train cancellations, and if you’re really lucky, getting stuck in the infamous M6 traffic jam. Everyday as though on autopilot we habitually follow our set route to various destinations, without noticing the stress and strain on the transport networks that we so heavily depend on. Our cells operate much like transport networks and these networks are used to execute specific functions. A train signal failure can make us late home for tea, but a fault in the cellular network can often become a deadly disease. This disease can take away the closest things to us; friends, family and even your life. This is CANCER.

Cancer – a disease which defies the rules of biology by stripping away the regulatory mechanisms that dictate when our cells are destroyed and when new cells are created. In normal cells, signalling information is transferred down the signalling network and passes through various checkpoints, like a train stopping at stations before it reaches its final stop. Certain proteins control the signalling network by interacting with its downstream partners to ensure the cell’s intended function is achieved. Cancer occurs mainly as a result of malfunctioning proteins involved in normal cell growth, causing sporadic cell growth that becomes harmful to the body.

Collectively known as ‘Ras proteins’, H-Ras, K-Ras and N-Ras, were amongst the first proteins described as having the capacity to control signalling networks that are involved in cell growth. Ras proteins are the hub of the cellular network and act like a switch. When the switch is ‘on’ Ras is activated, triggering a controlled cascade of signalling information along the pathway to activate proteins to function. The activity of Ras is partly regulated by the binding of a protein known as Son of Sevenless (Sos). 

Three decades have passed since the initial identification of Ras tumors and despite 30% of all human tumours known to have Ras mutations, there still remains no effective commercial therapeutic treatment for Ras mutant tumors. Understanding the mechanism of Ras activation via interactions with Sos remains unclear, and poses a challenge for effective drug designs. The aim of my research is to understand the interactions of the Ras: Sos complex using techniques such as Nuclear Magnetic Resonance (NMR) spectroscopy. NMR spectroscopy is a technique similar to MRI, but is mainly used to detect the structural changes of a protein at the binding site interface of protein-protein interactions.

The NMR spectrum of a protein gives rise to NMR signals that are then assigned to a specific position of the protein. These NMR signals can be imagined as tube stations of the London underground. Each station represents a unique location in London. Similarly, each NMR signal represents a specific position in the protein. If you need to go from the Northern line to the Piccadilly line, you will need to identify a specific station where both lines are linked together. Equally, the NMR signals allows me to identify specific regions of Ras where an interaction with Sos occurs. We have observed and assigned 99% of NMR signals from all of the functionally significant regions of K-Ras, the variant most strongly implicated in human malignancies. This work could be a significant step towards understanding how Ras controls many of the important signalling networks, which have been associated with cancer.

Why does this matter? Well the harsh reality is, that not only will cancer affect 1 in 3 of us during our life-time, but creating new and effective drugs is becoming more challenging and expensive. Cancer services alone cost the NHS around £5 billion annually. My PhD project will involve using a new NMR technique to monitor the direct binding between Ras and Sos proteins simultaneously, under the same conditions when a drug compound is added. This new technique will aid our endeavours in identifying potential drug compounds that disrupt the Ras:Sos interactions. I believe the technique can be commercially applicable by providing a simple and fast approach to filter out problematic compounds, making the pharmaceutical industry pipeline more cost-effective in the long term.

It might take a while to resolve a train signalling problem and like those working towards curing cancer, we believe there is light at the end of the tunnel. Understanding how Ras proteins are regulated is fundamental towards creating new anti-cancer therapies. My project aims to solve this problem. If successful, my project may influence new anti-cancer treatments to cure and improve the quality of life for cancer sufferers and their families.