487 Topical MEK inhibition as precision targeted chemoprevention

Cutaneous squamous cell carcinoma (cuSCC) comprises at least 20% of all non-melanoma skin cancers. Effective chemoprevention for cuSCC is lacking and high-risk cuSCC causes significant surgical morbidity. Previously, we conducted RNA-seq analysis of human cuSCC, which identified ETS2, a transcription factor in the ERK pathway, as an upstream regulator of cuSCC development. Consistent with this, our computational drug repositioning screen predicted the FDA-approved MEK1, 2 inhibitor, selumetinib, as a therapeutic for cuSCC based on its ability to reverse transcriptional signatures associated with cuSCC development. As a regulator of ERK activity, we reasoned MEK would be a viable chemopreventative target. Although systemic MEK inhibition suppresses tumor formation, systemic MEKi administration causes significant adverse effects. Here, we report the development of a topically formulated, metabolically labile MEK inhibitor, NFX-179, designed to potently and selectively suppress the ERK pathway in the skin prior to rapid degradation in the circulation. In our UV-induced model of cuSCC, topical application of NFX-179 gel reduced the formation of new cuSCCs by an average of 60% at doses of 0.1% and greater at 28 days. No systemic or skin toxicities were observed. Furthermore, we conducted a split-mouse randomized controlled study in 5 mice. NFX-179 0.5% gel was applied to half of the back and vehicle was applied to the other half of each of the UV-irradiated mice. Near complete suppression of cuSCC was observed only in the drug-treated area, demonstrating the targeted and local effect of the intervention. NFX-179 inhibits the growth of human cSCC cell lines in a dose-dependent manner and topical NFX-179 application penetrates human skin and inhibits ERK signaling in human cuSCC explants. Our data provide compelling evidence that topical application of NFX-179 is a safe, effective strategy for SCC chemoprevention in high risk individuals.