Transcriptome-guided drug repurposing identifies selumetinib for an aggressive epithelial cancer

Area of Science:

• Oncology
• Dermatology
• Pharmacology

Background:

• Recessive dystrophic epidermolysis bullosa-associated squamous cell carcinomas (RDEB-SCC) are aggressive with limited treatments.
• There is a critical need for novel therapeutic strategies for RDEB-SCC.

Purpose of the Study:

• To investigate selumetinib, a MEK inhibitor identified via computational screening, as a potential treatment for RDEB-SCC.
• To evaluate the in vitro and in vivo efficacy of selumetinib against RDEB-SCC.

Main Methods:

• Transcriptome-guided computational drug screening to identify selumetinib.
• In vitro assays assessing cell viability, ERK phosphorylation, epithelial-mesenchymal transition markers (E-cadherin, vimentin), motility, invasion, PD-L1, MHC-I, and cytokine expression.
• In vivo xenograft studies evaluating tumor growth and phospho-ERK levels.
• RNA sequencing to identify treatment response biomarkers (EGR1, FOS, DUSP6).

Main Results:

• Selumetinib reduced RDEB-SCC cell viability, ERK phosphorylation, and tumor cell invasion in vitro.
• It induced a mesenchymal-to-epithelial transition and modulated immune markers (PD-L1, MHC-I).
• In vivo, selumetinib suppressed tumor growth and decreased phospho-ERK levels, with EGR1, FOS, and DUSP6 identified as potential biomarkers.

Conclusions:

• Selumetinib demonstrates significant preclinical efficacy against RDEB-SCC.
• The findings support selumetinib's potential as a clinical candidate for RDEB-SCC treatment.