Experimental ERK Inhibitor Demonstrates Potential as Melanoma Therapy

A novel compound that blocks an overactive cell growth signal was found to be effective in advanced melanoma and other cancers in an early-stage clinical trial, the results of which were published by JCI Insight.

The experimental treatment was effective in melanoma and other cancers driven by BRAF or RAS mutations and may represent a new way to fight the deadly diseases. BRAF mutations cause cell growth signals to become overactive, thus driving cancer growth.

Included in the phase 1 trial were 26 patients who were treated with MK-8353, which blocks the ERK signaling protein.

ERK is the final step in the RAS-RAF-MEK-ERK signaling cascade and has been shown to drive cancer cell growth in drug-resistant melanoma and other cancers, according to the study.

The FDA has approved targeted therapies for melanoma and BRAF-mutated lung cancers, but most patients develop resistance and relapse due to ERK reactivation, the authors reported.

In the study, 3 of 15 patients whose results could be evaluated achieved a partial response after MK-8353 treatment. These patients were all diagnosed with BRAF-mutated melanoma.

Despite the small number of patients in the trial, the response rate was similar to findings from studies of other treatments. The authors of the current study noted that the lower response rate indicates that the novel ERK inhibitor should be used as a combination therapy rather than a standalone drug.

“The response rate that we saw for ERK inhibitors is reminiscent of the response seen with MEK inhibitors,” said lead researcher Stergios Moschos, MD. “We think, therefore, that ERK inhibitors cannot be given as single agents, just like MEK inhibitors. The question is: Which combination is best?”

Additionally, the researchers sought to determine proper dosing for MK-8353. Patients were able to tolerate MK-8353 400-mg twice per day without experiencing serious side effects, according to the study.

Due to potential toxicity concerns, future clinical trials should focus on developing different dosing schedules, according to the study. The authors suggest that MK-8353 should be administered once or twice per day every few days.

“This alternative approach may balance higher, though more temporal, suppression of pERK at the tumor tissue in favor of sparing sustained suppression of ERK signaling in normal tissues,” the authors wrote.

ERK has become a potential drug development target for multiple cancers. These new findings further confirm the need for ERK inhibitors as a way to fight cancer.

“ERK certainly stimulates factors that promote cancer growth,” said researcher Channing Der, PhD. “ERK is very complex, and it’s still surprisingly poorly understood, but what is very clear is that it is required for cancer growth, and that’s why there are a number of inhibitors in this pathway that are either approved, or under clinical evaluation. Clearly, drug companies for good reason have decided that this is an important pathway, let’s make inhibitors against it.”