The BRAF Inhibitor Vemurafenib Enhances UV-Induced Skin Carcinogenesis in Beta HPV38 E6 and E7 Transgenic Mice  Daniele Viarisio, Karin Müller-Decker, Jessica C. Hassel, Jean-Claude Alvarez, Christa Flechtenmacher, Michael Pawlita, Lutz Gissmann, Massimo Tommasino  Journal of Investigative Dermatology  Volume 137, Issue 1, Pages 261-264 (January 2017) DOI: 10.1016/j.jid.2016.08.030 Copyright © 2016 The Authors Terms and Conditions

Figure 1 Vemurafenib synergizes with HPV38 E6 and E7 in promoting UV-induced carcinogenesis. (a) Schematic diagram of the experimental procedure of long-term UVB irradiation. Experimental groups of 7-week-old wild-type (WT) FVB/N mice were fed either a normal diet (WT, n = 6) or a diet containing the BRAF inhibitor vemurafenib (Vem) (WT + Vem, n = 10); groups of age-matched K14 HPV38 E6/E7-Tg (HPV38-Tg) mice were also fed either a normal diet (HPV38-Tg, n = 21) or a diet containing Vem (HPV38-Tg + Vem, n = 21); all four groups were long-term UVB-irradiated as schematically shown. (b) Kaplan-Meier plot of skin lesion development over time in the WT and HPV38-Tg mice treated and untreated with Vem. The differences between the curves for the following animal groups were statistically significant, as determined by the log-rank test for group data: HPV38-Tg + Vem versus WT (P < 0.001), HPV38-Tg + Vem versus WT + Vem (P < 0.001), HPV38-Tg + Vem versus HPV38-Tg (P < 0.01), HPV38-Tg versus WT (P < 0.001), and HPV38-Tg versus WT + Vem (P < 0.001). (c) Mean number of lesions per animal in HPV38-Tg mice treated and untreated with Vem. The numbers of tumors were recorded weekly. The difference between the curves was statistically significant starting from week 22 (*P < 0.05, **P < 0.01, ***P < 0.001) as determined by the t-test for unpaired groups. (d) Kaplan-Meier plot of squamous cell carcinoma (SCC) development over time in the WT and HPV38-Tg mice treated and untreated with Vem. The differences between the curves for the following animal groups were statistically significant, as determined by the log-rank test for group data: HPV38-Tg + Vem versus WT (P < 0.001), HPV38-Tg + Vem versus WT + Vem (P < 0.001), HPV38-Tg + Vem versus HPV38-Tg (P < 0.001), HPV38-Tg versus WT (P < 0.05), and HPV38-Tg versus WT + Vem (P < 0.05). (e) SCC size in HPV38-Tg mice fed a normal diet (− Vem) and a diet containing Vem (+ Vem). The mean diameters of lesions that clearly appeared to be SCC (later confirmed by histology) are reported. The lesions were measured weekly. (f) Representative pictures of the dorsal skin of three HPV38-Tg mice (left) and three HPV38-Tg + Vem mice (right), 25 weeks after the start of UVB irradiation. (g) Hematoxylin and eosin staining of representative SCC sections from an HPV38-Tg mouse (left), with clear keratinization and an exophytic, verrucous-like growth pattern, and from an HPV38-Tg + Vem mouse (right), characterized by extensive keratinization and horn pearl formation, with abundant eosinophilic cytoplasm and prominent intercellular bridges. The mice were killed respectively 34 and 29 weeks after the beginning of the experiment. Scale bar = 2 mm. (h) Representative immunoblots showing phosphorylated ERK (phospho-ERK) and total ERK levels in lysates of dorsal skin keratinocytes of two different pairs of WT and HPV38-Tg mice. ERK, extracellular signal-regulated kinase; HPV, human papillomavirus. Journal of Investigative Dermatology 2017 137, 261-264DOI: (10.1016/j.jid.2016.08.030) Copyright © 2016 The Authors Terms and Conditions