Our milestones: the discovery of the NRAS signalling gene

In the latest in Our Milestones series, we go back to the 1980s – the dawn of a new era in cancer research – and look at how a team of Cancer Research UK researchers uncovered one of the key faulty genes that make cancer tick.

Public perception of cancer is often of a single disease, with a single cure. And until relatively recently, many doctors assumed that they just needed to work out the right mix of chemotherapy drugs and they’d be able to cure the disease.

In our most recent Milestones post we explored how, in the 60s and 70s, this ‘combination’ approach to chemotherapy made some real advances for some patients with certain forms of cancer, notably leukaemia.

But by the 1980s, it was becoming clear that more drugs did not necessarily equal more cures. Cancer was not one disease with one cause and one treatment.

Thankfully, around the same time, a different strategy was emerging. Laboratory researchers were starting to identify the faulty genes inside cancer cells. And this led to a new idea: could disrupting how they worked hold the key to beating cancer?

But to find out, first the genes had to be identified, and their workings uncovered. This is the story of how two young British scientists – Chris Marshall and Alan Hall – tracked down a gene that, when faulty, turned out to be a lynchpin for cancer cell growth.

Their discovery would help transform our understanding of the signals sent within cells that tell them to grow, and help to open the door to a new generation of ‘targeted’ cancer drugs.

From viruses to humans – tracking down the ‘cancer genes’

Professor Chris Marshall, part of the team that tracked down the NRAS gene

Our story starts in the late 1970s, when evidence began to emerge that at least some cancers were caused by faulty genes: researchers showed that human cells contained genes that were very similar to genes in viruses that cause cancers in animals.

It turned out that, under normal circumstances, these genes only kicked into action in normal cells when they were needed, telling cells to multiply to replace damaged and dead neighbours, or as part of normal growth. But  if these genes became altered, it could cause cancer.

Because of this cancer-causing ability, the defective versions of the genes were called ‘oncogenes’.

And by the early 80s, the race was on to find more of these troublesome genes and figure out what they were doing.

One example, which we’ve covered before in this series, is a gene called EGFR, first linked to cancer by researchers at our London Research Institute (now the Francis Crick Institute) in the early 80s. It ultimately led to the development of drugs like cetuximab, gefitinib and erlotinib.

We’re all going on an oncogene hunt

Around this time, elsewhere in London, two young, energetic scientists – Marshall and Hall – had just been recruited to The Institute of Cancer Research (ICR), and funded by one of Cancer Research UK’s predecessors: the Cancer Research Campaign.

They decided to search for oncogenes using a technique developed by US researchers, where DNA from cancer cells is inserted into healthy cells to see if it will make them cancerous.

This search for oncogenes required a range of scientific skills, but their backgrounds made them an ideal team. Marshall was fascinated by the behaviour of cells – the biological building blocks that make up our bodies. Meanwhile, Hall was a molecular biologist, interested in the genetic ‘nuts and bolts’ inside cells that made them tick.

They were keen to prove themselves and dreamed the dream of all explorers: to discover something new, something fundamental: in keeping with the scientific spirit of the time, they wanted to find their very own oncogene.

It sounds like a simple idea, but it was a trying time for the pair. They had no luck for almost a year. Even when they knew they’d sucessfully modified their laboratory grown cells with DNA from cancer cells, they didn’t find any signs of oncogenes.

The pressure was mounting, and The ICR’s head – Prof Robin Weiss – was getting impatient. Marshall and Hall were beginning to wonder if they were wasting their time.

As a last resort, they decided to analyse another 20 DNA samples and, if nothing panned out, they would drop the idea and focus on something else.

Then, they finally struck gold. DNA from two different tumour cells showed evidence of an oncogene. And they were quickly able to show that it was probably the same oncogene in the two different tumours.

And a close look at the DNA ‘recipe’ of their new gene revealed that it looked similar to two oncogenes, called HRAS and KRAS, which had recently been discovered by researchers in the US.  After some discussion with their US counterparts, Marshall and Hall decided to name this new gene NRAS.

They published their landmark discovery in the June 1983 issue of the journal Nature.

Researchers now know the 3D shape of RAS proteins.

It turns out that about 12 per cent of all human cancers contain a faulty HRAS, KRAS or NRAS gene, making these genes among the most mutated genes in cancer. And some cancer types are more likely to have a RAS mutation – such as pancreatic cancer – while in others, such as breast cancer, such faults are quite rare.

RAS oncogenes can also be cancer-specific: for example in pancreatic cancers that contain a RAS mutation, it is always KRAS that’s faulty. But in melanomas and leukaemias it’s usually NRAS. We still don’t know why different cancer types have different RAS mutations.

But their discovery in human tumours, momentous in itself, is only the start of the story. Once the genes’ identities had been uncovered, researchers were able to turn their attention to the next fundamental question: how do they cause cancer?

Sending signals

Thanks to the painstaking work of hundreds of cancer researchers – Hall and Marshall included – we now know the answer.

In healthy cells, the proteins made by RAS genes are switched on by incoming signals from the cell’s exterior, and then proceed to switch on other proteins like a molecular game of pass the parcel. This is known as an ‘intracellular signalling pathway’, and the end result is the activation of genes required for a cell to grow and divide.

In most of our cells, RAS proteins are usually inactive, and only turned on when the cell gets a signal to multiply.

But in cancer, the faulty RAS oncogene produces a defective protein that is always switched on. In turn, this means the signalling pathway is always active, leading to the unchecked frenzy of cell growth and division that defines cancer.

Having discovered NRAS, Chris Marshall’s lab went on to make the important discovery that RAS proteins control a key signalling pathway called the ‘MAP kinase’ pathway. We now know that, when it becomes active, RAS activates members of a second family of proteins called the RAF family, which then activate a protein called MEK, which in turn activates one called MAPK, ultimately setting the wheels in motion for cell division.

A simple diagram of the MAP Kinase pathway

And it turns out that, if any of the other parts of this pathway become ‘oncogenic’ and misbehave, a cell can become cancerous.

This seemingly simple mechanism – a defect that allows the cell to keep dividing endlessly – lies at the heart of most cancers. Indeed, this very independence from external growth signals is one of the so-called ‘hallmarks of cancer’.

Passing it on

The field of cell signalling has since exploded, with thousands of research papers published over the past three decades dissecting a whole host of pathways in intricate detail. Scientists who worked with Marshall and Hall went on to set up their own successful labs, forming their own highly active, collaborative (and sometimes competitive!) network of cell signalling researchers.

Through their discoveries, we are learning that how our cells communicate is not so much about straightforward lines of proteins talking to each other, as about intricate signalling webs – layers upon layers of feedback loops and cross-talk knitting together pathways once thought to be separate.

Untangling this, and understanding how it goes wrong in cancer, has been vital for developing new drugs to target overactive or broken signalling proteins. And this approach has already been successful in several new cancer treatments.

Although we don’t yet have cancer treatments that can directly switch off any of the RAS family members (for a variety of reasons – they’re particularly tricky targets for designing drugs against), many researchers around the world are working on it, and there are glimmers of hope on the horizon.

But even if we can’t target RAS itself, thankfully, other parts of the MAP kinase pathway are more amenable. For example drugs that block activation of MEK are now being tested in clinical trials, while drugs that block BRAF are now used to treat melanoma (you can read more about how we helped link BRAF to cancer in this Milestones post).

These are exciting times. Researchers are now translating the findings from the laboratory bench to patients in the clinic with so-called ‘targeted’ therapies.

We’ve come a long way from those two ambitious young scientists at The Institute of Cancer Research, hunting for oncogenes by looking for rogue cells in a Petri dish. But the basic principles of research are still the same: by understanding the fundamental molecular processes at work in cancer, we will come up with more effective cures.

And the more of this work we do, the sooner these cures will come.

Buddhini Samarasinghe is a science communications manager at Cancer Research UK.

Sadly, Professor Marshall died in August 2015. We’re grateful for his lifetime of pioneering science, his friendship and mentoring work with many of the leading cancer researchers here in the UK and beyond, and for his help in writing this post. [Updated KA 10/08/15]

Reference

• Hall A., Marshall C.J., Spurr N.K. & Weiss R.A. Identification of transforming gene in two human sarcoma cell lines as a new member of the ras gene family located on chromosome 1., Nature, PMID: http://www.ncbi.nlm.nih.gov/pubmed/6304521