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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 \u03b2 (TGF-\u03b2)\/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-\u03b2 signaling in ras-transformed metastatic epidermal keratinocytes (RT3 cells) harboring wild-type B-Raf and hyperactive Ras. PLX8394 decreased phosphorylation of TGF-\u03b2 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.<\/jats:p>","DOI":"10.1038\/s41388-023-02863-8","type":"journal-article","created":{"date-parts":[[2023,10,20]],"date-time":"2023-10-20T18:02:23Z","timestamp":1697824943000},"page":"3633-3647","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Inhibition of TGF-\u03b2 signaling, invasion, and growth of cutaneous squamous cell carcinoma by PLX8394"],"prefix":"10.1038","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1709-8633","authenticated-orcid":false,"given":"Elina","family":"Siljam\u00e4ki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2934-0645","authenticated-orcid":false,"given":"Pilvi","family":"Riihil\u00e4","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9389-2911","authenticated-orcid":false,"given":"Ujjwal","family":"Suwal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6743-6736","authenticated-orcid":false,"given":"Liisa","family":"Nissinen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5068-2842","authenticated-orcid":false,"given":"Pekka","family":"Rappu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markku","family":"Kallajoki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2421-9368","authenticated-orcid":false,"given":"Veli-Matti","family":"K\u00e4h\u00e4ri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2978-805X","authenticated-orcid":false,"given":"Jyrki","family":"Heino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,10,20]]},"reference":[{"key":"2863_CR1","first-page":"62","volume":"16","author":"V Madan","year":"2016","unstructured":"Madan V, Lear JT, Szeimies R-M. 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