Forschung & Innovation
Publikationen
Transcriptome-guided drug repurposing identifies selumetinib for an aggressive epithelial cancer
PMU Autor*innen
Sonja Dorfer, Roland Zauner, Christina Guttmann-Gruber, Victoria Reichl, Michael Ablinger, Stefanie Gruner, Julia I Hummel, Josefina Piñón Hofbauer, Ulrich Koller, Iris K Gratz, Johann W Bauer, Verena Wally
Alle Autor*innen
Sonja Dorfer, Roland Zauner, Christina Guttmann-Gruber, Victoria Reichl, Michael Ablinger, Stefanie Gruner, Julia I Hummel, Josefina Piñón Hofbauer, Ulrich Koller, Iris K Gratz, Johann W Bauer, Verena Wally
Fachzeitschrift
JOURNAL OF INVESTIGATIVE DERMATOLOGY
Kurzfassung
Squamous cell carcinomas (SCC) arising in patients with recessive dystrophic epidermolysis bullosa (RDEB) are highly aggressive and often cause premature death. Current treatment options are limited, highlighting the need for innovative drug development concepts. Through transcriptome-guided computational drug screening, we identified selumetinib, a mitogen-activated protein kinase kinase (MEK) inhibitor, as a candidate drug for RDEB-SCCs. To verify the therapeutic potential of selumetinib against RDEB-SCCs, we assessed its efficacy in vitro and in vivo. In vitro, selumetinib decreased tumor cell viability, significantly reduced phosphorylation of extracellular signal-regulated kinase (ERK), and induced a mesenchymal-to-epithelial phenotypic shift, as indicated by increased E-cadherin and decreased vimentin expression. Functionally, it impaired tumor cell motility and invasion. Moreover, selumetinib significantly decreased programmed death-ligand 1 (PD-L1) and increased major histocompatibility complex-I (MHC-I) levels and modulated the expression of immune-related cytokines. In vivo, selumetinib significantly suppressed tumor growth and reduced phospho-ERK levels in xenograft tumors. RNA sequencing identified early growth response protein 1 (EGR1), fos proto-oncogene (FOS), and dual-specificity phosphatase 6 (DUSP6) as candidate biomarkers of treatment response. Selumetinib, identified by computational drug screening, demonstrates efficacy against RDEB-SCCs in vitro and in vivo, suggesting its potential for clinical use.