A newly discovered pain-processing pathway could lead to alternative treatments for chronic pain. The new treatments could even make use of existing cancer drugs that block the epidermal growth factor receptor (EGFR). This receptor, long a target in cancer therapies, has only recently received attention for its therapeutic potential against pain.

A recent study implicating EGFR in pain processing found that this receptor and its natural ligand, epiregulin (EREG), interact to heighten pain perception. This finding, derived from experiments with mouse models, suggests that both EGFR and EREG could be suitable therapeutic targets for chronic pain in humans. Even if existing drugs that interfere with EGFR/EREG interactions were to fail to manage pain effectively, they could serve as a starting point for engineering more useful variants.

There is likely sufficient incentive to develop alterative pain killers that could replace opioids, given that opioids carry the risk of addition and undesirable side effects.

Details from the new study appeared August 7 in the Journal of Clinical Investigation, in an article entitled “Epiregulin and EGFR Interactions Are Involved in Pain Processing.” The article reported that EGFR blockers, routinely given to lung cancer patients to inhibit tumor growth, were as potent analgesics as morphine in mouse models of inflammatory and chronic pain. The article also attributed the analgesic effect to a mechanism thought to regulate pain, but never before evaluated with behavioral or cellular models specifically relevant to pain processing.

“EREG-mediated activation of EGFR enhanced nociception through a mechanism involving the PI3K/AKT/mTOR pathway and matrix metalloproteinase-9,” wrote the article’s authors. “Moreover, EREG application potentiated capsaicin-induced calcium influx in a subset of sensory neurons. Both the EGFR and EREG genes displayed a genetic association with the development of chronic pain in several clinical cohorts of temporomandibular disorder.”

The study, which was led by McGill’s Luda Diatchenko, Ph.D., arrived at this last finding, the association with temporomandibular disorder, a human chronic pain syndrome, after they searched for evidence that EGFR contributes to pain in a clinical population. Three human cohorts of temporomandibular disorder were assessed in four case-control association analyses on a panel of 358 pain-relevant candidate genes. “The association of EGFR and EREG with chronic pain in a clinical cohort,” the articles’ authors noted, “is an important translational complement to our mouse data and supports the potential value of targeting EGFR for chronic noncancer pain management in humans.”

“We know this pathway is relevant in humans,” explained Dr. Diatchenko. “This discovery is very exciting and important; it's really going to help us extend our knowledge about the molecular pathophysiology of chronic pain.

“We now need to answer two questions: Is this really effective for human chronic pain? And what are the side effects associated with the dosage needed to efficiently treat it?”

The McGill team hopes that its findings will lead to clinical trials in order to assess the potential of EGFR inhibitors used in cancer therapy as pain management therapeutics. Repurposing existing drugs to treat diseases other than those they were designed for can be advantageous, because the toxicity of these compounds is well understood, making them a fast and relatively inexpensive way to develop new treatments.

If these cancer therapeutics don't turn out to be useful for pain management, they could nevertheless be used as the foundation to develop new drugs. “By re-engineering or tweaking these drugs, the road to getting to a useful pain treatment will be much, much shorter,” noted Jeffrey Mogil, Ph.D., of the department of psychology at McGill and the study's co-lead author.

“This is quite exciting as EGFR is one of the most studied proteins in all of biomedicine because of its important role in cancer,” Dr. Mogil added. “But aside from a few clinical case studies, a role for EGFR in pain has never been shown.”

“…we find that clinically available small molecule EGFR inhibitors targeting the tyrosine kinase site of the EGFR receptor, including gefitinib and lapatinib, are effective analgesics in mice for inflammatory and neuropathic pain,” the authors of the current study concluded. “Since we find that EREG is the primary endogenous activator of EGFR-related pain hypersensitivity, our data suggest that an effective treatment strategy may be the selective inhibition of EREG over other endogenous EGFR ligands. Directly targeting EREG may result in a reduced side-effect profile when compared with currently available EGFR-inhibition strategies.”

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