Researchers have discovered a biological mechanism to encourage a rare eye cancer to respond to drug treatment more effectively.
In a recent study, a team from Thomas Jefferson University found that only by targeting both the G protein-coupled receptor (GPCR) and its mutated internal molecular switch can uveal melanoma cell signaling be disrupted.
G proteins are intercellular molecular switches that tell the cell whether to grow and divide, produce a chemical signal or communicate messages to other cells. GPCRs are cell receptors that detect signals from outside the cell and then interact with these G proteins inside the cell.
Usually, G proteins can turn on and off with their own regulation mechanisms. But in uveal melanoma, a rare eye cancer, more than 90% of patients have mutations in a type of G protein, dubbed Gαq/11, which leads to the protein staying in its constitutively active form and unable to turn off. This causes aberrant cancer signaling pathway activation and increased cell proliferation seen in this cancer and others.
“Inhibiting these GPCRs in combination with other inhibitors or drugs could be a way to therapeutically target uveal melanoma,” Philip Wedegaertner, Ph.D., professor of biochemistry at Thomas Jefferson University and the study's corresponding author, explained to Fierce.
Researchers investigated the role of mutated Gαq/11 in uveal melanoma cell lines and the effects on cancer cell activity. They found that mutations caused cancer cell proliferation, which was abolished when treated with a combination of a GPCR antagonist and a Gαq-specific inhibitor.
Although the GPCR antagonist alone was not enough to reverse the cancer cell proliferation, it did sensitize the uveal melanoma cells to respond to the Gαq-specific inhibitor, according to Wedegaertner. The inhibitor, YM-254890, acts by binding directly to Gαq and stabilizing it in its inactive state.
The drug combo was able to shift the Gαq/11-mutated cells stuck with the G protein in an active state over to the inactive state seen in normal cells.
“We could use less of this inhibitor for the G protein, and possibly better inhibit uveal melanoma cells without as much toxic effect,” Wedegaertner suggested.
Wedegaertner explained that the research group is starting to explore testing the drug combination and the lower dose levels of the inhibitor in mouse models, with the goal of eventually translating the research to humans.
“I think this GPCR or other GPCRs could be targets potentially in combination with other drugs,” he added. “The hope would be that other people would become interested in this idea.”
Although GPCRs play an important role in many cancers and popular drugs such as GLP-1 agonists act on these receptors, the role in uveal melanoma has not been well explored.
Novartis has been developing an antibody-drug conjugate with a Gαq/11 inhibitor payload, which showed disease control in nearly 82% of patients with uveal melanoma and reduced tumor size in 71% in a phase 1 study in the summer. However, the ADC isn't currently listed on Novartis' oncology pipeline.