When Julian Downward began his PhD in 1982, he had no idea how profoundly it would transform cancer treatment. But one evening, as he and his supervisor Mike Waterfield examined long-awaited data from their institute’s mainframe, he recalls: “it was pretty clear that this was something really big.”

Back then, much about cancer and how cells grew was still a mystery. What made cells divide, and what stopped them? And when this went wrong, could it be corrected? Many believed that answering these questions could reveal new ways to treat cancer – a disease driven by uncontrolled cell division.

“I’d just finished a biochemistry degree. It seemed natural to do a PhD next – and I thought studying how cell growth is controlled was a really promising area,” says Downward. He joined the Waterfield lab at our London Research Institute – now part of the Francis Crick Institute – to study small proteins secreted by cells, called growth factors.

“Mike’s big idea was that, if growth factors were part of life’s normal growth regulatory system, maybe they were going wrong in some way in cancer,” Downward explains. He focused on one known as epidermal growth factor, or EGF. “We knew that EGF circulated around the body and could control the growth of cells. But, at the time, we didn’t really know how.”

Finding the receptor 

Discovered in the 1960s, EGF had been shown to trigger cell growth by binding to a receptor on the cell surface – but how the receptor worked was still a mystery. Downward set out to isolate and study it. A year after he began, he and his colleagues had purified the receptor – now called EGFR – from human cells and began manually determining its amino acid sequence – months of meticulous work. 

He reasoned that comparing the sequence to those of other, better understood proteins might reveal clues as to how EGFR functioned. But in the early 1980s, that meant using offline databases distributed by post every six months. “It was incredibly labour-intensive. The US National Institute of Health would collate and distribute databases of sequences, in tape form, by post. We’d have to load these onto the Institute’s mainframe,” he says. In between updates, newly published sequences would be typed in manually, from the pages of academic journals.  

Eventually, having inputted his EGFR sequence, one dark London evening in November 1983, after months of whirring and chuntering, the computer finally returned results – and they were astonishing. 

Viral connection 

To understand why, we need to step briefly into the world of viruses.  

Viruses reproduce by hijacking a cell’s machinery, and – in certain rare circumstances – some can inadvertently trigger cancer. The first cancer-causing virus was discovered in chickens in 1911, but for decades this phenomenon was dismissed as a curiosity, until the 1970s brought renewed interest as scientists realised these viruses sometimes carried altered versions of normal cell growth genes. 

It appeared that, during their evolution, these viruses had “stolen” host genes that controlled growth, and by reusing them inappropriately, triggered cancer in infected cells. 

Back at the London Research Institute in 1983, Downward’s computer analysis had revealed that part of EGFR’s amino acid sequence almost exactly matched a viral protein called v-Erb-B, made by Avian Erythroblastosis Virus, which causes leukaemia and sarcomas in chickens. 

“It was very striking when it came up, just how perfect the match was,” Downward recalls. The finding linked two once-separate fields – growth factor biology and tumour viruses – and hinted that a cell’s own EGFR might cause cancer if it became overactive. “As soon as we saw that link and realised that EGFR-like proteins could cause cancer, then it was immediately obvious that this could be a therapeutic opportunity.” 

In other words, if signals sent by EGFR turned out to cause a cell to multiply out of control, could blocking them stop it? 

Their discovery, published in Nature in February 1984, fired the starting gun on a global effort to understand and target EGFR. 

Three generations of treatments 

Over the following decades, research revealed that overactive EGFR signalling did indeed turn out to drive several cancers – and drugs that blocked the receptor proved able to slow tumour growth and increase patients’ survival. Forty years on, EGFR-targeting therapies are a cornerstone of modern cancer treatment, especially in lung cancer. 

“This has definitely transformed how we treat the disease,” says Charlie Swanton, Cancer Research UK’s chief clinician and an oncologist at University College London Hospital. “EGFR drugs are often particularly effective for lung cancers in non-smokers. Virtually all these cancers are adenocarcinomas, which we’re increasingly realising are driven by disruptions in pathways triggered by EGFR.” 

Following Downward’s discovery, pharmaceutical companies began developing drugs to inhibit EGFR. By the early 2000s, researchers had identified specific mutations that permanently switched EGFR on, fuelling tumour growth. Around the same time, the first generation of EGFR inhibitors – including gefitinib and erlotinib for lung cancer, and cetuximab and panitumumab for bowel cancer, and head and neck cancer – became available.  

A landmark 2008 trial showed people with EGFR-mutant lung cancer lived longer on gefitinib than on chemotherapy. This was a key moment for personalised medicine, as oncologists could now tailor treatment based on a tumour’s genetics. 

And by 2020, US data showed lung cancer death rates falling sharply as EGFR therapy for lung cancer became widespread, particularly in the form most strongly linked to EGFR mutations – non-small cell adenocarcinomas. This was clear evidence that these treatments were having a real-world impact. 

But, as Swanton notes, “The real challenge is that – effective as these drugs are – they can’t cure the disease.” Tumours almost always evolve to resist treatment. “We really need to understand more about the remaining cells that are able to resist treatment, and where they come from, so we can find ways to eliminate them completely”. 

Overcoming resistance 

Downward has spent his career unpicking this problem. Now leading the Oncogene Biology Lab at the Francis Crick Institute, he has helped chart the intricate network of signalling proteins – including RAS, RAF and MEK – that transmit growth signals inside cells, many of which are now drug targets themselves. 

“Those first-generation EGFR drugs had a dramatic effect initially, but we saw that most of the patients were becoming resistant after a year or so,” he says. “And that really kicked off a focus on understanding drug resistance.” 

Within years, researchers identified resistance mutations and developed new generations of drugs to overcome them, such as osimertinib. 

“The newer EGFR drugs are very good indeed,” says Swanton. “I've got patients with advanced lung cancer who have been on these drugs for well over five years now.” Previously, such patients could expect to survive around a year. 

Still, resistance remains a formidable obstacle. “However much you engineer a drug to be perfect at blocking EGFR, you can't account for what else is going on in the cell,” Downward says. His focus now is on overcoming drug resistance by combining different therapies – in particular, immunotherapy. 

“One of the things that overactive EGFR signalling does very effectively is not just cause cancer cells to grow, but to also change the whole environment around them – they start secreting proteins called cytokines that switch off the immune system,” he explains. “We’re now looking at how we can combine targeted drugs with newer immune therapies to get around this." 

Downward’s recent findings in mice suggest this could be a powerful strategy, and demonstrate how continued research into cancer’s inner secrets will continue to drive progress – just as his initial discovery of EGFR’s link to cancer, four decades ago, helped open the door to modern cancer medicine. 

“In terms of drugs we’ve got available, the oncologist’s toolbox has got some really smart tools in it now. And what gives me hope is how we can learn how to combine them, to continue to make a real difference to patients.”