Targeting the Ras protein – a small but exciting step forward

Ras is one of the most important proteins in cancer

As we report on our news feed today, researchers at US pharma company Genentech have announced that they’ve designed a number of small molecules that can stick rather weakly to a tiny protein called Ras.

At first glance, this may not seem like a particularly exciting thing to have done.

But Ras is, in fact, one of the most important proteins in cancer, and when it goes wrong it can cause extremely aggressive cancers. As a result, researchers have been trying to develop drugs to target it for over 25 years.

So, although this is only a small step, it’s in many ways as significant as the first step of an infant. There’s a long, unsteady journey ahead, but things are finally moving.

Let’s look at what Ras is, how it’s involved in cancer, and why this announcement is so important.

What is Ras and what does it do?

Ras is found in all our cells. It’s a small protein that sits on the inner surface of a cell’s membrane, waiting to be activated by external signals.

In a way, it works a bit like the aerial socket in the wall of your living room, receiving signals from elsewhere (from receptors – TV aerial-like proteins that stick out of our cells) and passing them on to their eventual destination – in this case, the cell’s nucleus.

There are hundreds of similar proteins in our cells that are part of these signalling networks – if you want a glimpse at their sheer complexity, have a quick look at this diagram:

Click to enlarge

The way these networks operate, however, is very different from the electrical cables of a TV aerial, and (if you’ll excuse the mixed metaphor) more like a Newton’s Cradle.

Newton's cradle - a bit like cell signalling

So when Ras becomes activated, it physically bumps into other proteins and switches them on.

These, in turn, bump into others and switch them on. This chain of events ultimately ends up in the nucleus – the cell’s ‘control centre’ – where the message finally arrives and tells specific genes to be switched on.

This is where the cancer connection comes in – the chain of events set off by Ras ultimately turns on genes that tell the cell to start growing, dividing, and spreading.

Under normal circumstances, Ras only starts transmitting signals under extremely tightly controlled circumstances.  But in cancer, it loses the need to be stimulated from outside, and constantly broadcasts its signals.

It’s as if your aerial socket, detached from the aerial on your roof, had gained a life of its own, and was forcing its own distorted, deadly TV shows onto your TV screen.

Ras in cancer

Years of research has shown that over a quarter of all cases of cancer are driven by faulty Ras proteins. And in some types of cancer – notably pancreatic cancer – it’s more like nine out of ten cases.

Clearly, a drug that switches Ras proteins off in cancer cells could be a potent weapon against a range of cancers.

Drugging Ras

For the last 25 years, researchers have tried to find a way to do just that, with little success.

They have, however, learnt a huge amount about how Ras and the proteins in its network work. Much of this knowledge – particularly of proteins like BRAF (which, like Ras, becomes permanently switched on in certain cancers) – has yielded targeted drugs like vemurafenib, which has recently been approved to treat melanoma.

But Ras itself has remained stubbornly resistant to the best efforts to target it. To understand why, we need to look at how drugs are developed, and how a new technique – ‘fragment-based’ drug design – is broadening the range of targets that researchers can work on.

A spanner in the works

In recent years, drug design has involved looking for a particular region of a target protein that carries out a particular reaction, and literally sticking something in it to stop it working, like sticking a faulty key in a lock.

This works very well for proteins like enzymes, which tend to have a precise and defined ‘lock’, called the active site, into which it is usually possible to stuff a molecular ‘key’ and mess things up.

But Ras doesn’t work like that. When Ras interacts with one of its partners, it passes on its message through an interaction between its unique three-dimensional shape and that of its target – more like ‘hand in hand’ than ‘key in lock’.

Trying to target the interaction between two proteins, rather than a small crevice, was generally thought to be too challenging for current research techniques. Enter fragment-based drug design.

From locks and keys to sticky stuff

Rather than starting with large and complicated ‘keys’ to try to find one that will fit nicely into the protein’s ‘lock’, a fragment-based approach starts off with much smaller, simpler molecules, and looks for ones that stick much more weakly to the target.

The development of fragment-based drug discovery has relied on access to extremely sensitive techniques, with weird and wonderful names like ‘surface plasmon resonance’ and ‘nuclear magnetic resonance’, to measure these weak interactions.

Once researchers have found these small slightly-sticky molecules, they can gradually build them up, making them larger and more complicated until they’ve created something that could conceivably be used as a drug.

So using tiny fragments and sensitive detection techniques, the research team at Genentech were finally able to find something that sticks to one of Ras’s interacting surfaces – something that had eluded scientists using traditional drug discovery techniques.

What exactly do Genentech’s molecules do?

In their announcement, made at the American Society of Cell Biology’s annual meeting in Denver, a Genentech team led by Joachim Rudolph, Weiru Wang, and Guowei Fang, announced that they’d created molecules that stick to a specific region of Ras – one that’s involved exchanging signals with another protein called SOS. They also showed that these molecules could prevent Ras from receiving signals from SOS.

This is, as we said above, real progress. As the researchers themselves say in the conference abstract, “[this] represents a breakthrough finding that will offer a new direction” in research to develop cancer treatments to target Ras.

But, as ever in cancer research, there are caveats.

Call screening

Alert readers will have spotted one of these already. Genentech have found molecules that stop Ras from receiving signals. But in cancer, Ras is stuck in a state of permanent activity, so blocking incoming calls, so to speak, doesn’t really solve the main problem of shutting up errant Ras proteins.

However, Professor Julian Downward, a senior researcher at our London Research Institute who has spent much of his career studying Ras, can see a way to exploit this. “What future research might attempt”, he told us, “is to use this as just an anchor point and ‘build outwards’ towards other regions of the Ras protein with more complicated molecular structures”, reaching around the protein to target the areas of interest.

He cautions that this will take time and effort, and that success isn’t necessarily a given. “There’s still a lot of work to be done to figure out how to turn off the faulty Ras proteins inside cancer cells to treat patients with the disease,” he told us.

Nevertheless, he said, “this new research represents a very exciting ‘proof-of-concept’ that Ras can indeed be targeted.”

What happens next?

So clearly, despite the obvious excitement, this is a long way from being anywhere near a drug that can be tested in a living organism. But it opens the door for researchers worldwide to redouble their efforts to target Ras – a protein that many in the research community have regarded as ‘undruggable’.

It’s also another (small) victory to be chalked up for fragment-based drug discoverers. Professor Martin Drysdale leads the Cancer Research UK-funded drug discovery programme at the Beatson Institute in Glasgow, which specialises in this approach, and also works on Ras. He told us the fragment-based method was becoming ever-more popular.

“Fragment-based drug discovery, is gaining traction around the world as a way to target cancer proteins that have been regarded as ‘undruggable’. In recent years this approach has led to the targeted therapy vemurafenib, which was recently approved in the US to treat certain forms of skin cancer”, he told us.

“It’s great to hear about Genetech’s progress in targeting Ras. The coming years will be extremely exciting, as discoveries in the lab can be harnessed using approaches like fragment-based discovery to create more experimental drugs for clinical trials that we hope will benefit patients.”

We certainly hope so.

Henry