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Inhibition of TGF-β signaling, invasion, and growth of cutaneous squamous cell carcinoma by PLX8394
Elina Siljamäki1,2, Pilvi Riihilä3,4, Ujjwal Suwal1,2
1MediCity Research Laboratory, University of Turku, Tykistökatu 6A, FI-20520, Turku, Finland.
Abstract:
Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer. The prognosis of patients with metastatic cSCC is poor emphasizing the need for new therapies. We have previously reported that the activation of Ras/MEK/ERK1/2 and transforming growth factor β (TGF-β)/Smad2 signaling in transformed keratinocytes and cSCC cells leads to increased accumulation of laminin-332 and accelerated invasion. Here, we show that the next-generation B-Raf inhibitor PLX8394 blocks TGF-β signaling in ras-transformed metastatic epidermal keratinocytes (RT3 cells) harboring wild-type B-Raf and hyperactive Ras. PLX8394 decreased phosphorylation of TGF-β receptor II and Smad2, as well as p38 activity, MMP-1 and MMP-13 synthesis, and laminin-332 accumulation. PLX8394 significantly inhibited the growth of human cSCC tumors and in vivo collagen degradation in xenograft model. In conclusion, our data indicate that PLX8394 inhibits several serine-threonine kinases in malignantly transformed human keratinocytes and cSCC cells and inhibits cSCC invasion and tumor growth in vitro and in vivo. We identify PLX8394 as a potential therapeutic compound for advanced human cSCC.
Insights
The B-Raf inhibitor PLX8394 shows promise for treating advanced cutaneous squamous cell carcinoma (cSCC). This drug effectively inhibits key signaling pathways, reducing tumor growth and invasion in preclinical models.
Area of Science:
- Oncology
- Dermatology
- Molecular Biology
Background:
- Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer with a poor prognosis.
- Ras/MEK/ERK1/2 and transforming growth factor β (TGF-β)/Smad2 signaling pathways are implicated in cSCC invasion.
- Laminin-332 accumulation and accelerated invasion are linked to these signaling pathways in transformed keratinocytes.
Purpose of the Study:
- To investigate the efficacy of the B-Raf inhibitor PLX8394 in blocking TGF-β signaling and inhibiting cSCC progression.
- To evaluate PLX8394's effects on key molecular targets and cellular processes involved in cSCC invasion and growth.
Main Methods:
- Treatment of ras-transformed metastatic epidermal keratinocytes (RT3 cells) with PLX8394.
- Assessment of TGF-β signaling pathway components (TGF-β receptor II, Smad2) and p38 activity.
- Measurement of matrix metalloproteinase (MMP-1, MMP-13) synthesis and laminin-332 accumulation.
- Evaluation of PLX8394's effect on human cSCC tumor growth and collagen degradation in a xenograft model.
Main Results:
- PLX8394 effectively blocked TGF-β signaling by decreasing phosphorylation of TGF-β receptor II and Smad2.
- PLX8394 reduced p38 activity, MMP-1 and MMP-13 synthesis, and laminin-332 accumulation in RT3 cells.
- PLX8394 significantly inhibited human cSCC tumor growth and in vivo collagen degradation in xenograft models.
Conclusions:
- PLX8394 inhibits multiple serine-threonine kinases in malignant keratinocytes and cSCC cells.
- PLX8394 demonstrates potent inhibition of cSCC invasion and tumor growth both in vitro and in vivo.
- PLX8394 is identified as a potential therapeutic agent for advanced human cSCC.
