Topical NFX-179 Inhibits MEK Activity, May Prevents SCC

Pre-clinical experiments in mouse models found that a gel formulation of NFX-179 reduced the formation of new cutaneous squamous cell carcinomas by up to 92% at the highest doses.

Topical NFX-179 may prevent the development of cutaneous squamous cell carcinoma in pre-clinical models, according to a new article published in Science Translational Medicine.

“Our previous work showed that the canonical mitogen-activated protein kinase (MAPK) signaling pathway is important for the development of cutaneous squamous cell carcinoma,” says  Kenneth Tsai, MD, PhD, vice chair of Research Pathology and senior member of the Cancer Biology & Evolution Program at Moffitt Cancer Center in Tampa, Fla., in a news release. “Our new study expanded on this, by showing that drugs that target the extracellular signal-regulated kinase (ERK) MAPK pathway, including MAP2K / MEK inhibitors, may be an effective approach to prevent the development of cutaneous squamous cell carcinoma.”

While several MEK inhibitors are already approved to treat advanced cancers, such as melanoma and non-small cell lung cancer, these drugs must be given orally and are associated with side effects that would limit their continuous use, particularly in the context of cancer prevention.

Tsai and a team of researchers sought to develop a drug to specifically target the MEK1/2 proteins that could be applied topically on a regular basis. Because of its continuous use, they also needed the drug to have minimal to no side effects. Therefore, the drug had to penetrate the upper epidermal and lower dermal layers of the skin while retaining high potency and being rapidly cleared from circulation to limit side effects.

The researchers designed and screened over 100 compounds and identified the drug NFX-179 that fit their requirements. They performed a series of pre-clinical experiments in mouse models and discovered that a gel formulation of NFX-179 reduced the formation of new cutaneous squamous cell carcinomas by up to 92% at the highest doses. Additionally, the effects of the NFX-179 gel were localized, as inhibition of cutaneous squamous cell carcinoma development was observed only in areas that were treated with the drug, and no systemic toxicities were observed.

“Our data provide compelling rationale for using metabolically labile topical MEK inhibitors such as NFX-179 as an effective strategy for cutaneous squamous cell carcinoma chemoprevention. NFX-179 gel appears safe, tolerable and highly efficacious in pre-clinical model systems,” Tsai says.

The study was conducted in collaboration with NFlection Therapeutics and researchers at Stanford University.