The Story of EGFR

How an unlikely duo used snake venom and radioactive iodine to discover the first known tumor-causing proteins, leading to a revolution in cancer treatment.

    5 Things to Know About EGFR

  1. Many different types of tumors have increased EGFR activity. EGFR mutations crop up in cases of non small cell lung cancer (NSCLC) as well as colorectal cancer, head and neck cancer, breast cancer, and others.
  2. In healthy cells, EGFR signals when it is time to copy DNA and divide. When EGFR is mutated, this process is thrown off, and can lead to unchecked cell growth and cancer.
  3. Tumors with lots of EGFR proteins are more likely to grow quickly, spread to other tissue, and resist treatment with standard chemotherapies.
  4. Testing for an EGFR mutation requires a recent tumor sample.
  5. There are a number of different EGFR inhibitors on the market, which target EGFR in slightly different ways. They work to slow tumor growth and prevent the spread of cancer to other parts of the body. While effective, unfortunately, many patients develop resistance to these drugs over time. Overcoming that resistance through, for example, using several drugs in combination, is an active area of research.

When do cells reproduce and what do they become? Answering these questions enables researchers to create therapies targeting particular kinds of cancers. An upper-class Italian woman and a working-class kid from Brooklyn, who met in St. Louis, took the first steps toward finding the chemicals that control cellular reproduction in the early 1950s. In the words of the committee that gave Rita Levi-Montalcini and Stanley Cohen the Nobel Prize 30 years later, they showed how “skilled observer[s] can create a concept out of apparent chaos.”

Control switch of the skin

EGFR, short for epidermal growth factor receptor, is a protein molecule of the tyrosine kinase family found on the cell surface. Like a key turning a lock, molecules outside the cell called growth factors bind with EGFR to activate it. This then initiates a cascade of chemical reactions inside the cell that energize it and encourage the cell to divide.

Up until Cohen and Levi-Montalcini discovered growth factors, it had been thought that hormones – substances that signaled to cells how to behave – were produced only in specialized glands and released into the bloodstream. In fact, all human cells can produce chemicals that send signals both within cells and between them. Levi-Montalcini and Cohen discovered the first two growth factors to be identified: Nerve Growth Factor, or NGF, and Epidermal Growth Factor, or EGF. EGFR is a protein found in all human cells that EGF binds to. When EGF binds to EGFR (both molecules have closely related siblings that perform similar functions, but for simplicity we will mostly neglect the siblings) it sets in motion a series of changes in cells. It affects how cells develop – what kind of cells they turn into, whether they keep dividing, and how long cells stay alive. In the last few decades, biologists have been mapping out the pathways that explain how these changes take place. EGFR does not have one single straightforward effect; what it does depends on what other proteins are present, and which parts of one another they bind to.

EGFR is important in cancer care because many different types of tumors have increases in EGFR activity. For example, a mutation in a gene that codes for EGFR plays an important role in non-small-cell lung cancer, which is the leading cause of cancer death in the United States (and accounts for almost nine out of 10 lung cancers). Understanding how EGFR works allowed researchers to develop a drug that targets its function. Gefitinib (marketed as Iressa) was approved by the Food and Drug Administration (FDA) in 2003. Even though most patients didn’t respond to gefitinib, as researchers delved into the 10 percent of patients who did respond – in some cases quite quickly and well – to the drug, they found that they had similar types of mutations to their EFGR gene. (These patients tended to mostly be non-smokers who had developed adenocarcinoma, Asians, and women.) However, many patients who initially responded very well to the drug then went on to develop resistance. Understanding how that resistance works is an active area of research. To understand the roots of that research, it’s worth going back to the beginning of research into growth factors.

Rita Levi-Montalcini was born in 1909 in Turin, an industrial city at the edge of the Alps, in northern Italy. Her father was an electrical engineer and mathematician, and her mother a painter. As a child in the First World War, she thought about becoming a nurse. Giovanna, her childhood nanny, died of stomach cancer when Levi-Montalcini was 20, and so she decided to become a doctor. She graduated from medical school in Turin in 1936. Levi-Montalcini was Jewish, but stayed in Italy during the war, determined to keep doing science. She fled Turin with her parents, to move to a small country house, where she rebuilt her laboratory. She was using chicken eggs for her biological experiments, but there was a shortage of eggs, so after using an egg to experiment on, she would scramble it and eat it. After the Allies took over in August 1944, she went to work in a refugee camp, treating typhus.

A critical regulatory element

EGFR is an important player in a variety of cellular activities. In the early stages of embryonic development of humans and many other animals, the activation of this receptor helps instruct different kinds of cells where to go, guiding the shape of the organism. In childhood and adult life, binding EGFR can signal it is time to make more DNA and for the cell to divide. In times when cells need to replicate at an unusually high rate or volume, such as when the body’s skin is having an immune response, EGFR is critical for guiding this process.

After the war, she went to St. Louis, Missouri to work in the laboratory of Viktor Hamburger, at Washington University. Levi-Montalcini described working with Hamburger as a paradise, “sheer pleasure” after her secluded and solitary work during the war. She came to believe – long before she had evidence to prove her hypothesis – that the mouse tumors she was studying were releasing a “growth factor of unknown nature.” To figure out what the factor was, she wanted to use a technique for which the laboratory in St. Louis lacked necessary equipment. So she decided to visit an old friend from Italy who was now running her own laboratory at the medical school of Rio de Janeiro.

And so Levi-Montalcini flew from St. Louis to Italy (on a quick visit back home) to Brazil carrying two tumor-bearing mice with her, shifting them from her purse to an overcoat pocket. The effect she was looking for had, she wrote, “given a first hint of its existence in St. Louis; but it was in Rio de Janeiro that it revealed itself…in a theatrical and grand way.” She put small fragments of the mouse tumors in a “semisolid drop of rooster plasma and embryonic extract”. Nothing happened. She then tried an intermediate step of transferring the mouse tumors into chick embryos. The result surprised her. She remembered “astonishment and wonder” when she found that the tumors grew a halo of nerves “like the rays of the sun” in only twelve hours.

She returned to St. Louis, still unable to figure out just what the compound was that was causing this dramatic growth. It was then that she met Stanley Cohen, who had recently moved to St. Louis. Cohen, or Stan, as she would call him, had been born to Russian Jewish immigrants in Brooklyn. His father was a tailor; he went to Brooklyn College, which was tuition-free at the time, and then got a job in a milk processing plant. Cohen became a biochemist; he remembers that “[I] knew very little about neuro-embryology, and [Hamburger and Levi-Montalcini] knew very little about biochemistry.” Levi-Montalcini said she often asked herself “what lucky star caused our paths to cross.” Until Cohen left for Tennessee in 1959, Levi-Montalcini would write, she and Cohen “met many times each day in that room in front of a desk fitted in between a window, in the shadow of a great red tree, and lab benches covered with vials and test tubes.”

Cohen would later say that even in college he wondered, “how does an egg turn into a chicken or a frog or a person? My only insight into the problem was the thought that it was necessary to understand the chemical reactions inside the egg and embryo and not simply observe biological structures.” Cohen and Levi-Montalcini tried using snake venom to purify what they had come to call Nerve Growth Factor, or NGF. But instead, they found that the snake venom itself was a rich source of NGF. After another decade of work, Cohen came to understand that the snake venom not only contained NGF, but also another growth factor, which he dubbed EGF in 1965.

When EGFR goes out of control

Mutations in the genes that code for the EGFR receptor can result in more copies of the protein being produced or in a higher frequency of signaling than is needed. This results in an amplification of the signal that tells the cell to divide, which can lead uncontrollable growth and, in some cases, cancer. Studies have shown that by measuring the amount of EGFR a person is producing, they can predict if a cancer will recur or not with varying levels of accuracy depending on the type of cancer.

In the 1970s, Cohen kept trying to figure out just what EGF was made of, and how it caused growth. Even though he and Levi-Montalcini would end up with the Nobel Prize for this work, at the time, they had the field to themselves. She would describe the decade as a “private hunting ground.”

By the late 1970s, Cohen’s and other groups were figuring out what receptors EGF binds to in human cellular membranes. He would tag EGF with a radioactive isotope of iodine, which let him keep track of how it acted in a controlled line of human skin tumor cells called A-431 cells. By 1979, he identified a “major protein band of molecular weight 150,000” – what would come to be called EGFR.

Part of the reason EGFR is so important is because it is an example of something called a tyrosine kinase. Tyrosine kinases can act as switches in cells, because they can effectively take a phosphate group – a crucial salt – from ATP, a chemical that functions as an energy source in cells, and add that phosphate to various proteins. Gefitinib, the first drug developed that fights mutant EGFR proteins, acts by inhibiting this process, called phosphorylation. Other, similar drugs – among them erlotinib, dasatanib , and nilotinib (marketed as Tarceva, Sprycel, and Tasigna respectively) – have been developed that try and accomplish the same thing in slightly different ways. Researchers hope that these drugs might work more effectively in combination with one another, and prevent the development of resistance.

These drugs are all fundamentally alike. They are all examples of what are called “small-molecule drugs,” a category that includes most drugs. Their smallness matters because it means that they can pass through cell membranes, and therefore can be delivered orally, for the most part. About 90 percent of the mutations of EGFR’s tyrosine kinase domain (the part of the EGFR gene that codes for the part of the EGFR protein that acts as a tyrosine kinase) fall into in four types, so it’s relatively easy to test for the mutation. For individuals who have the mutation, gefitinib and its sibling drugs effectively bind to EGFR, keeping it from acting as a signaling pathway that leads to tumor growth.

Getting cell division back on track

When treating cancers that can be traced back to a mutation in the EGFR genes, the majority of new therapies involve two main forms of “EGFR inhibitors”: monoclonal antibodies, and tyrosine kinase inhibitors. If the receptor is blocked by a molecule that looks like the growth factor molecule the receptor is used to binding with, but that doesn’t actually activate the receptor, the cell won’t get the message to divide. This can slow tumor growth and keep them from traveling to other parts of the body. EGFR inhibitors exhibit varying levels of selectivity, permanence, and will have different side effects in different people. Always consult with your oncologist before embarking on any path of treatment.

By the early 1980s, researchers were realizing that inhibiting EGFR expression could be a promising way to fight some tumors. Cohen and Levi-Montalcini, about to receive the Nobel Prize, were now no longer alone in working in the field they’d started. In 1984, another team first sequenced the DNA that codes for a precursor version of EGFR. Only in 2002 did a team succeed in using X-ray crystallography to view the structure of EGFR’s tyrosine kinase domain.

Besides the small-molecule drugs, another kind of drug, called a monoclonal antibody, has also been used to fight cancers caused by EGFR over-expression. Cetuximab (marketed as Erbitux) has been used against types of colorectal cancer, head and neck cancer, while trastuzumab (marketed as Herceptin) has been used against breast cancers. (Trastuzumab targets ERBB2, a slightly different type of tyrosine kinase domain from EGFR.) Monoclonal antibodies are fundamentally different from the chemically-synthesized small-molecule drugs. Instead, monoclonal antibodies are created in genetically engineered mice that contain human genes. They can sometimes be used in combination with small-molecule drugs.

Cohen, now retired, remains in Tennessee. Levi-Montalcini would become the first Nobel Laureate to live to be 100 years old. She died in 2012. Thousands of researchers now work to understand the growth factors that she and Cohen first identified in St. Louis. Levi-Montalcini would remember Cohen once telling her “you and I are good, but together we are wonderful.” The coming together of an expert on embryonic development and an imaginative biochemist was what it took to begin understanding the proteins that shape the development of cells, both in normal cellular development, and in cancerous cells. And understanding what specifically is going wrong in cancerous cells can help develop treatments: as Fred Bunz writes in Principles of Cancer Genetics, “mutations in target genes can predict therapeutic responses.” Just as Montalcini and Cohen’s discovery of EGF was crucial in understanding how growth factors work, so too is current work on EGFR crucial to understanding how to narrowly target specific genetic mutations in trying to treat cancer.

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