MEK Inhibition Shows Promise in Aggressive EB-Linked Skin Cancers
Key Takeaways
Selumetinib reduced tumor viability and ERK phosphorylation in squamous cell carcinomas cells arising in recessive dystrophic epidermolysis bullosa and xenografts.
The drug reversed EMT and enhanced tumor immunogenicity, suggesting potential compatability with immunotherapies.
Authors said the findings support selumetinib as a repurposed therapeutic candidate for clinical evaluation in RDEB-SCC.
A transcriptome-driven drug repurposing strategy has identified selumetinib as a potential therapeutic candidate for aggressive squamous cell carcinomas (SCCs) arising in recessive dystrophic epidermolysis bullosa (RDEB).
Researchers used computational screening via the LINCS database to identify selumetinib as a compound capable of reversing the gene expression signature associated with RDEB-SCC. In vitro, selumetinib significantly reduced ERK phosphorylation in vitro, while impairing impairing tumor cell viability and reverseing epithelial-to-mesenchymal transition (EMT). Tumor cell motility and invasion also decreased.
Immunomodulatory data showed selumetinib treatment lowered PD-L1 levels while increasing MHC-I expression and promoting pro-inflammatory cytokine release, including IFN-γ and IL-12. In xenograft mouse models, oral selumetinib suppressed tumor growth without observed toxicity, reducing final tumor volume by half vs. controls. Despite showing comparable in vitro toxicity in both tumor and healthy keratinocyte lines, selumetinib's dual antitumor and immunomodulatory activity suggests clinical relevance. Topical formulations or alternative MEK inhibitors like trametinib, which may present fewer cutaneous side effects, warrant exploration.
"Selumetinib, identified by computational drug screening, demonstrates efficacy against RDEB-SCCs in vitro and in vivo, suggesting its potential for clinical use," the authors wrote.
Source: Dorfer S, et al. Journal of Investigative Dermatology. 2025. Doi:10.1016/j.jid.2025.12.010