GRACE :: Treatments & Symptom Management


Dr West

What is EGFR and Why Do We Target It?

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The topic of what is EGFR is one that really deserves to have been covered here from the beginning, but somehow I skipped to the drugs and what they do in cancer patients. It’s time to take a step back and discuss EGFR and why it’s been an important target in cancer.

EGFR stands for Epidermal Growth Factor Receptor, and it can be targeted from the outside of the cell by intravenous monoclonal antibodies against the target protein (also known as a ligand) binding portion of the cell, or from the inside of the cell by oral small molecule inhibitors against the part of the receptor called the tyrosine kinase domain that activates the intracellular machinery:


(click to enlarge)

EGFR is actually just one of a family of four receptors, called human epithelial receptors, or the HER family, that each are activated by different ligands or in some cases no known ligand. EGFR is another name for HER1, and HER2 is a receptor that is very important in many patients with breast cancer.

HER family

These receptors are activated by one of their activating ligands and pair up with another receptor in the HER family, either one of the same receptors (homodimerization) or a different one (heterodimerization). This process leads to the activation of the back end of the receptors and a cascade of activities inside of the cell.

EGFR primer update\EGFR intracellular activities

These activities are quite complex, but the overall effect is to increase activation of many genes and facilitate cell cycle progression, so overall this promotes cell growth and division. Overall, this leads to many activities that are good for the cell but bad for the person if it’s a cancer cell, because it increases the cell’s likelihood of survival, turns of self-regulating cellular self-destruct programming (called apoptosis), facilites the cell’s ability to invade other tissues and metastasize, and even increases protein signals that promote angiogenesis, the development of increased blood supply to the area.

Drugs that block the receptor portion on the outside of the cell, or the tyrosine kinase portion on the inside of the cell, inhibit activity of the entire cascade.

Inhibiting the EGFR cascade

Though the figure above highlights the intracellular activity of the tyrosine kinase inhibitors (TKIs) like tarceva (erlotinib) and iressa (gefitinib), the same concept holds true for blocking this cascade with extracellular monoclonal antibodies against the actual ligand-binding portion of EGFR.

One thing that has been unique to the story for EGFR TKIs is the special activity of this class of agents with activating EGFR mutations. We’ll cover that next.

4 Responses to What is EGFR and Why Do We Target It?

  • jimmy112199 says:

    Dr. West:
    I heard that BIBW2992 is very good after TARCEVA gains resistance, could you give some comments


  • Dr West
    Dr. West says:


    BIBW is an irreversible inhibitor of EGFR and the related HER2 receptor. It may be beneficial beyond what we see with drugs like tarceva and iressa, but other irreversible inhibitors and/or combined EGFR/HER2 inhibitors were hyped as likely miracles over the past few years, only to fade into oblivion when they proved to be far less convincingly beneficial than their promoters had claimed.

    I’m very reluctant to make any presumptions about the real utility of these treatments until they’re tested properly in real patients. In many cases, the insinuation that these medications are a major breakthrough are made by people who study cancer in a lab setting. I have a real problem with lab people making very grandiose claims about how great a new treatment will be based on how it works in a test tube or animal model, because these are very, very artificial scenarios compared with actually treating real people with an evolving cancer.

    I will be very happy to review the clinical results with this agent once they’re available to be reported for a reasonable number of patients, but until then I remain very skeptical of agents that are hyped far ahead of any actual proven benefit. Nobody’s talking about the other handful of drugs that were also generating buzz for the same claim 2-3 years ago (by some of the same people), then showed no real value at all.

    This isn’t to say that BIBW-2992 will show the same fate, but making a claim is easy: showing it’s backed by evidence is the hard part.

    -Dr. West

  • Paula C. says:

    Dr. West,

    My father has mucinous BAC,a very advanced case. He starts gefitinib tomorrow, but we are unsure if he is a positive match for it because the mutation tests haven’t come back yet. My question is if he’s not a positive match for the drug are there any other options available other than chemo. His Dr. said chemo is probably not a good choice because he probably wouldn’t survive it.

  • Dr West
    Dr West says:

    Unfortunately, other than a trial of an EGFR inhibitor like Iressa or Tarceva, and perhaps a trial of single agent chemotherapy, options are pretty limited. Some cases of mucinous BAC are so relentless and resistant that I’m not sure that there is anything on earth that will make a meaningful difference, at least nothing we know about right now.

    However, beyond EGFR, there is a chance that some people with mucinous BAC will harbor an ALK rearrangement that can be tested for (there are labs that do this specific test), and if that were positive, the oral agent crizotinib would often be VERY helpful, and the chemo agent pemetrexed (Alimta) might also be useful (some studies suggest it has particular activity in ALK-positive lung cancers). I understand that he may be very debilitated, but single agent Alimta is among the better tolerated chemotherapy approaches.

    -Dr. West

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