A protein best known for driving certain skin and lung cancers may also play a central role in chronic pain that follows nerve injury, according to a study from the University of Texas MD Anderson Cancer Center published Aug. 29 in Science Signaling.
The protein, BRAF, is a well-established cancer driver and the target of several approved cancer drugs. Researchers co-led by Shao-Rui Chen and Hui-Lin Pan, both of MD Anderson's Department of Anesthesiology and Perioperative Medicine, found that after a nerve injury, BRAF relocates from peripheral nerves to synapses in the spinal cord, where it boosts the activity of NMDA receptors, a class of proteins that, when overactive, are known to amplify and sustain pain signals traveling toward the brain.
Blocking BRAF Eased Pain in Injured Animals
The team tested the pathway from several directions in animal models of nerve injury. Deleting the Braf gene reduced how long heightened pain sensitivity persisted after injury, while directly activating BRAF triggered pain sensitivity even in animals with no nerve damage at all, evidence the researchers say points to BRAF as a driver of the pain response rather than simply a bystander. Treating injured animals with vemurafenib and selumetinib, two BRAF- and MEK-pathway inhibitors already approved for treating cancer, reduced their sensitivity to touch, pressure and heat. Notably, the drugs had no effect on pain responses in animals without nerve injury, suggesting they were correcting an injury-specific malfunction rather than dulling pain signaling broadly. The researchers also examined human spinal cord tissue and found patterns consistent with the animal findings, lending support to the idea that the mechanism is relevant beyond mice.
Because BRAF inhibitors are already approved for cancer treatment, this discovery raises the possibility of rapidly repurposing existing therapies to reduce the level of pain signals entering the spinal cord.
Hui-Lin Pan, MD Anderson Cancer Center
Chronic neuropathic pain, the kind that follows nerve damage from surgery, diabetes, chemotherapy or injury, is notoriously difficult to treat and often responds poorly to standard painkillers. A drug-repurposing path is attractive because it could shortcut the yearslong process of developing and safety-testing an entirely new compound, since BRAF inhibitors already have established human safety and dosing data from oncology use.
Still, the results described here are preclinical: the pain-reduction findings come from animal models, and while human tissue samples supported the underlying biology, no patient has yet been treated with a BRAF inhibitor for nerve pain in a clinical trial. The researchers say further work is needed to determine what triggers BRAF's move to the spinal cord in the first place, along with appropriate dosing and delivery methods and possible side effects, before the approach can be tested in people. MD Anderson said clinical trials are the logical next step to determine whether targeting BRAF can safely reduce neuropathic pain in patients.
