EGFR – Wanna be starting something?

For many, the 1980s represent social unrest and wardrobe disasters. But amidst the strikes and the legwarmers, the 1980s gave us much to be thankful for. For cancer scientists, it was a Renaissance period – a decade during which cancer research came of age and (unlike many of us) got a proper haircut.Cancer Research UK was at the heart of this maturation, so as part of Our Milestones series, we thought we’d go back and revisit a discovery that not only spawned a whole new field of cancer research, but led directly to the development of drugs that are used to treat cancer patients today.

(I’ve had) The time of my life

It was 1983, and the study of rare viruses that caused tumours was all the rage. Although we now know differently, many researchers at that time believed that all cancers were caused by infections, and many labs around the world were hunting for them. Strange as it may seem now, the idea our own cellular machinery going wrong could cause cancer was still in its infancy.

Scientists at London’s Imperial Cancer Research Fund laboratories (now Cancer Research UK’s London Research Institute) were making crucial advances in this field and the labs were buzzing with excitement and activity. Against this backdrop, a young scientist called Julian Downward was interested in a relatively unknown protein made by our cells, known as epidermal growth factor receptor or EGFR for short.

At the time, researchers had discovered that EGFR could control cell division in certain types of cell. But only a handful of labs around the world were even remotely interested, and linking this protein to cancer was a long way off. Nevertheless, Downward and his colleague Dr Mike Waterfield were intrigued by EGFR and wanted to understand how it worked.

Get into the groove

Proteins are made of long chains of smaller building blocks called amino acids.  The exact order of amino acids in the chain causes it to twist, tangle and loop, producing a distinctive three-dimensional structure.

This gives each protein its ‘personality’, allowing it to do its proper job in a cell. So to reveal the secrets contained within EGFR’s nooks and crannies, Dr Downward had to work out its exact amino acid sequence – something that had hadn’t been done before.

He started by isolating large quantities of EGFR from human cancer cells, using innovative techniques pioneered by colleagues in his lab. Next, he took the chemical equivalent of a sledgehammer and smashed EGFR up into tiny pieces.

These were then fed, one by one, into a machine developed by researchers in the lab called a gas-phase sequencer, which chewed them up and spat out their amino acid sequence. Finally, Downward had what he needed and his detective work could begin.

What a feeling

He started by asking whether his amino acid sequences were present in other molecules. Proteins that share similar arrangements of amino acids along their length often do similar jobs inside cells, so was this the case with EGFR?

Again, he was in the right place for the job as his benchmate, Geoff Scrace, was maintaining one of the few existing databases of all known protein sequences. Downward fed in his EGFR sequence data and waited.  His Eureka moment finally came three months later when the computer came up with a match – EGFR was almost identical to v-erb-B, a protein produced by a virus that causes cancer in chickens.

To Downward’s amazement, this cancer-causing virus protein was simply a neatly trimmed version of our own EGFR. This was a huge shock. It suggested that altering a cell’s own proteins could propel cancer growth. The findings proved that “the seeds of cancer are within us” as Nobel-prize winning scientist J. Michael Bishop famously proposed.

Downward’s work was published in the prestigious journal Nature where, like a nerdy version of Michael Jackson’s chart-topping album Thriller, it caused a sensation within the research community.

Labs investigating the role of EGFR in cancer suddenly mushroomed all over the world, propelling EGFR biology to the forefront of cancer research. It wasn’t long before changes in EGFR were linked to a myriad of cancer types and a sister protein, HER2, was discovered to play a critical role in certain types of breast cancer.

These results, together with others from scientists around the world, prompted a question that would change the face of cancer therapeutics:  If molecules like EGFR and HER2 propelled cancer growth, would blocking them kill tumours?

With this, the targeted therapies revolution was born.

Never gonna give you up

Fast forward to today. Rick Astley may have made an inexplicable comeback for the amusement of bored office workers, but Downward’s work has matured into sophisticated cancer drugs including erlotinib (Tarceva), gefitinib (Iressa), cetuximab (Erbitux) and trastuzumab (Herceptin) – all which aim to block EGFR or HER2 activity in cancer cells.

When asked to reflect on the implications of his work, Downward admits that even he was taken by surprise by the impact of his findings. When the match on the database came up, he told us,

“I knew that we were onto something very exciting but little did I know that EGFR would turn out to be such an important cancer target.”

It’s difficult to over-estimate the impact of this new wave of research. Until this point, cancer scientists and doctors had a very limited understanding of cancer – and this was reflected in the relatively harsh and untargeted cytotoxic chemotherapy used to treat the disease.

The realisation that the key to better and more effective cancer treatments lay not in ever-increasing doses of toxic chemicals, but in a detailed understanding of cancer’s inner workings was a realisation that is now making a difference to the lives of cancer patients around the world.

And to keep the momentum going, we’ve launching our Stratified Medicine Programme to help ensure that in the future, all people with cancer receive treatment tailored to the genetic makeup of their tumour. It’s our way of continuing what we started.

The EGFR story is a shining example of how fundamental research can evolve, and we are immensely proud to have been part of it.

Safia Danovi

Reference:

Downward J, Yarden Y, Mayes E, Scrace G, Totty N, Stockwell P, Ullrich A, Schlessinger J, & Waterfield MD (1984). Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences. Nature, 307 (5951), 521-7 PMID: 6320011