MediCity Research Laboratory, University of Turku, Tykistökatu 6A, FI-20520, Turku, Finland.
Department of Life Technologies and InFLAMES Research Flagship, University of Turku, FI-20014, Turku, Finland.
Oncogene. 2023 Dec;42(49):3633-3647. doi: 10.1038/s41388-023-02863-8. Epub 2023 Oct 20.
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.
皮肤鳞状细胞癌（cSCC）是最常见的转移性皮肤癌。转移性 cSCC 患者的预后较差，这强调了需要新的治疗方法。我们之前曾报道，转化的角质形成细胞和 cSCC 细胞中 Ras/MEK/ERK1/2 和转化生长因子β（TGF-β）/Smad2 信号的激活导致层粘连蛋白-332 的积累增加和侵袭加速。在这里，我们表明，下一代 B-Raf 抑制剂 PLX8394 阻断了携带野生型 B-Raf 和高活性 Ras 的 ras 转化的转移性表皮角质形成细胞（RT3 细胞）中的 TGF-β 信号。PLX8394 降低了 TGF-β 受体 II 和 Smad2 的磷酸化，以及 p38 活性、MMP-1 和 MMP-13 的合成以及层粘连蛋白-332 的积累。PLX8394 显著抑制了人 cSCC 肿瘤的生长和异种移植模型中体内胶原的降解。总之，我们的数据表明，PLX8394 抑制了恶性转化的人角质形成细胞和 cSCC 细胞中的几种丝氨酸/苏氨酸激酶，并抑制了 cSCC 的体外和体内侵袭和肿瘤生长。我们将 PLX8394 鉴定为晚期人 cSCC 的潜在治疗化合物。
