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Development of a MEK inhibitor, NFX-179, as a chemoprevention agent for squamous cell carcinoma
Kavita Y Sarin1, John Kincaid2, Brittney Sell3
1Department of Dermatology, Stanford University Medical Center, Stanford, CA 94063, USA.
Abstract:
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer. Although cSCC contributes to substantial morbidity and mortality in high-risk individuals, deployment of otherwise effective chemoprevention of cSCC is limited by toxicities. Our systematic computational drug repurposing screen predicted that selumetinib, a MAPK (mitogen-activated protein kinase) kinase inhibitor (MEKi), would reverse transcriptional signatures associated with cSCC development, consistent with our genomic analysis implicating MEK as a chemoprevention target. Although systemic MEKi suppresses the formation of cSCC in mice, systemic MEKi can cause severe adverse effects. Here, we report the development of a metabolically labile MEKi, NFX-179, designed to potently and selectively suppress the MAPK pathway in the skin before rapid metabolism in the systemic circulation. NFX-179 was identified on the basis of its biochemical and cellular potency, selectivity, and rapid metabolism upon systemic absorption. In our ultraviolet-induced cSCC mouse model, topical application of NFX-179 gel reduced the formation of new cSCCs by an average of 60% at doses of 0.1% and greater at 28 days. We further confirmed the localized nature of these effects in an additional split-mouse randomized controlled study where suppression of cSCC was observed only in drug-treated areas. No toxicities were observed. NFX-179 inhibits the growth of human SCC cell lines in a dose-dependent manner, and topical NFX-179 application penetrates human skin and inhibits MAPK signaling in human cSCC explants. Together, our data provide a compelling rationale for using topical MEK inhibition through the application of NFX-179 gel as an effective strategy for cSCC chemoprevention.
Insights
Topical NFX-179 gel effectively prevents cutaneous squamous cell carcinoma (cSCC) formation in mice by inhibiting the MAPK pathway, offering a safer chemoprevention strategy for skin cancer.
Area of Science:
- Oncology
- Dermatology
- Pharmacology
Background:
- Cutaneous squamous cell carcinoma (cSCC) is a prevalent skin cancer with significant morbidity.
- Current chemoprevention strategies for cSCC are limited by systemic toxicities.
- The MAPK pathway is implicated in cSCC development, suggesting it as a therapeutic target.
Purpose of the Study:
- To develop a targeted chemoprevention agent for cSCC with reduced systemic toxicity.
- To evaluate the efficacy and safety of a novel topical mitogen-activated protein kinase kinase inhibitor (MEKi), NFX-179, for cSCC chemoprevention.
Main Methods:
- Computational drug repurposing identified selumetinib as a potential MEKi for cSCC.
- NFX-179, a metabolically labile MEKi, was designed for topical application.
- Efficacy was assessed in a UV-induced cSCC mouse model, with localized effects confirmed in a split-mouse study.
- Human SCC cell lines and cSCC explants were used to confirm NFX-179's mechanism of action and skin penetration.
Main Results:
- Topical NFX-179 gel significantly reduced cSCC formation by 60% in mice.
- The chemopreventive effects of NFX-179 were localized to the application site, with no observed toxicities.
- NFX-179 demonstrated dose-dependent inhibition of human SCC cell growth and inhibited MAPK signaling in human cSCC explants.
Conclusions:
- NFX-179 is a potent and selective topical MEKi with potential for cSCC chemoprevention.
- Localized NFX-179 application offers a promising strategy to mitigate cSCC risk without systemic side effects.
- Further clinical investigation of topical NFX-179 gel for cSCC chemoprevention is warranted.
