From People to Mice to Flies: A Protein Implicated in Cancer Also Plays a Role in Pain

EGFR

Genetic variation in a protein called epidermal growth factor receptor is associated with chronic pain in people—and inhibiting this protein with currently available drugs blocks pain in mice. Image credit: ssilver/123RF Stock Photo.

Drugs that quiet the activity of epidermal growth factor receptor (EGFR), a protein that plays a role in the growth and survival of cells, are widely used to treat some types of lung, pancreatic, colorectal, and breast cancers. Interestingly, case reports and clinical trials have found that people who take these drugs report feeling less pain and a significant improvement in quality of life.

While researchers originally thought these positive effects on pain occur because the drugs shrink the size of tumors, recent studies have shown this is not the case, since the benefits remained even when the tumors did not shrink. This suggested that EGFR inhibitors may work to relieve pain in ways that have little to do with any impact on the cancer itself.

Now, a new study—the first to systematically assess the role of EGFR in pain—confirms that EGFR inhibitors do indeed relieve pain in a manner that is completely separate from how they combat cancer.

The research finds that genetic mutations in EGFR and related molecules are associated with temporomandibular disorder (jaw pain) in humans. And, the new work reports that EGFR inhibitors available for use in patients improve different types of pain in mice, and offers an explanation as to why.

“This is a remarkably interesting and really impressive paper. It is a very comprehensive study that uses human genetics, mouse models [of pain], and even Drosophila [fruit flies] to show quite convincingly that EGFR plays a role in [pain],” says Theodore Price, University of Texas at Dallas, US, a pain researcher who was not involved in the study.

The research, led by Jeffrey Mogil and Luda Diatchenko, from McGill University in Montreal, Canada, was published in the September 1, 2017 issue of the Journal of Clinical Investigation.

From humans…
The team didn’t start out studying the role of EGFR in pain, explains Diatchenko. Initially, the researchers were looking more broadly for any genetic changes that might be associated with pain.

They searched for single-letter changes in the genetic code (these alterations are known as single nucleotide polymorphisms or SNPs) that were associated with temporomandibular disorder. They looked to a group of 127 women with the condition and compared them to 231 individuals without pain who were used as control subjects.

Of 358 genes that appeared relevant to pain, SNPs in the EGFR gene and a molecule that activates EGFR, called epiregulin (EREG), were the most strongly associated with TMD. This was also the case when the researchers looked at two additional groups of female TMD patients.

…to mice…
Based on these findings, the researchers decided to look more closely at the role of EGFR in pain. So they tested what happened when they gave drugs that inhibit EGFR to mice who had experimental pain—either acute pain or chronic pain—caused by nerve damage or by the injection of painful inflammatory molecules.

They found that the drugs had a very strong pain-relieving effect in nearly all the types of experimental pain tested in the study. In fact, the relief they provided was similar to that seen with morphine.

…and even to flies!
To see if EGFR acted similarly in different animals, the research team then turned to Drosophila—the humble fruit fly.

When they eliminated the fly version of EGFR in pain-sensing neurons, the flies were less sensitive to being touched with a heated probe, which is one way to test pain in these creatures. When they put EGFR back into the neurons, this effect was reversed.

“We started from human data and then asked if mice have a similar involvement of EGFR and EREG in pain. The answer was yes. Then we went further down the evolutionary tree to Drosophila and again the answer was yes,” Diatchenko says.

How does it all work?
The researchers then discovered how EGFR contributed to pain, once again turning to mice. The team hypothesized that EGFR would be more active in the mice with chronic pain.

And indeed this was the case: EGFR showed higher levels of activity in the neurons that receive pain signals coming from the body and relay them into the spinal cord. The group went on to identify a number of molecules whose levels change after the receptor is activated.

“Our findings have uncovered a whole new pain pathway that deepens our understanding of the pathophysiology of chronic pain,” says Diatchenko.

Excitement over EGFR
People are excited about the prospects of relieving pain by targeting EGFR with drugs, especially since these drugs already exist for the treatment of cancer, Diatchenko said. Repurposing an existing drug for a new use is much faster than developing an entirely new drug from scratch.

Another benefit is that, unlike opioids, drugs that affect EGFR don’t carry risks of dependence, constipation, and breathing suppression. Although a proportion of people using EGFR inhibitors develop a rash, it is easily treatable, she adds.

The researchers are now planning a clinical trial of EGFR inhibitors for pain, likely starting with cancer patients who are already taking these drugs, Diatchenko says. The team will assess whether patients’ pain reports are related to both the genetic changes identified in the current study and levels of EREG in the blood.

“Now is a wonderful time to be finding new pain targets [molecules that drugs can affect to decrease pain] given the major emphasis on the non-opioid analgesics that are badly needed,” says Price. The current study opens up the exciting possibility of drugs that could have a combined effect on cancer and the pain caused by cancer, he adds.

To read about the research in more detail, see the related IASP Pain Research Forum news story here.

Allison Marin is a neuroscientist-turned-science writer who resides in Pittsburgh, US.