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Soo Park, MD
Soo Park, MD
Posted: Thursday, February 1, 2024
According to research findings published in the journal Oncogene, Elina Siljamäki, PhD, of the University of Turku, Finland, and colleagues found the next-generation, small-molecular BRAF inhibitor plixorafenib (PLX8394) simultaneously inhibited the activity of several key pathways in cutaneous squamous cell carcinoma. This agent was initially developed as a potential therapy for melanoma and lung cancer.
“In our earlier studies, we have observed that two signaling proteins in the cell, transforming growth factor-β [TGF-β] and Ras proto-oncoprotein, play a key role in the spread of cutaneous squamous cell carcinoma. In this study, we showed that plixorafenib, which was developed to inhibit the Ras signaling pathway, also blocked the activation of the TGF-β pathway and the growth of human cutaneous squamous cell carcinoma in mouse models,” explained Dr. Siljamäki in an institutional press release.
Researchers used three-dimensional spheroid cultures of transformed RT3 keratinocytes, which harbor wild-type B-Raf and hyperactive Ras, and spheroid co-cultures of RT3 cells and skin fibroblasts. They found that low micromolar concentrations of plixorafenib, previously shown to be nontoxic in in vivo experiments, inhibited phosphorylation of Smad2 and TGF-β receptor II and p38 activation. Consequently, plixorafenib decreased MMP-1 and MMP-13 expression and laminin-332 accumulation by RT3 cells as well as inhibited RT3 cell invasion. Orally administered plixorafenib inhibited growth and invasion of human cutaneous squamous cell carcinoma in vivo in a xenograft model.
“Our results show that plixorafenib is a very promising candidate for a clinical trial for treating local or metastatic cutaneous squamous cell carcinoma,” stated study coauthor Vel-Matti Kähäri, MD, PhD, also of the University of Turku.
Disclosure: The study authors reported no conflicts of interest.
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