The development of keratinocytic skin tumors, presumably attributable to paradoxical activation of the MAPK pathway, represents a relevant side effect of targeted therapies with BRAF inhibitors (BRAFis). The role of cutaneous papillomavirus infection in BRAFi-associated skin carcinogenesis, however, is still inconclusive. Employing the Mus musculus papillomavirus 1 (MmuPV1) skin infection model, the impact of BRAFis and UVB exposure on papillomavirus induced skin tumorigenesis was investigated in immunocompetent FVB/NCrl mice. Systemic BRAF inhibition in combination with UVB light induced skin tumors in 62% of the MmuPV1-infected animals. In contrast, significantly fewer tumors were observed in the absence of either BRAF inhibition, UVB irradiation or virus infection, as demonstrated by lesional outgrowth in 20%, 5% and 0% of the mice, respectively. Combinatory exposure to BRAFis and UVB favored productive viral infection, which was shown by high numbers of MmuPV1 genome copies andE1^E4spliced transcripts and an abundance of E6/E7 oncogene mRNA and viral capsid proteins. BRAF inhibition, but not viral infection or UVB light, activated ERK1/2, whereas γH2AX expression, inducible by UVB light, remained unaltered by BRAFis. These results provide experimental evidence that BRAF inhibition and UVB irradiation synergistically promote MmuPV1-induced skin tumor development in vivo. This indicates an alternative pathway by which papillomavirus skin infection may contribute to BRAFi-associated skin tumorigenesis.
角蛋白细胞性皮肤肿瘤的发展，推测归因于MAPK通路的反常激活，是BRAF抑制剂靶向治疗的相关副作用。然而，皮肤乳头瘤病毒感染在BRAF抑制剂相关皮肤癌发生中的作用仍无定论。本研究利用小鼠乳头瘤病毒1型皮肤感染模型，在免疫正常的FVB/NCrl小鼠中探究了BRAF抑制剂与UVB暴露对乳头瘤病毒诱导皮肤肿瘤发生的影响。系统性BRAF抑制联合UVB照射在62%的MmuPV1感染动物中诱发了皮肤肿瘤。相比之下，在缺乏BRAF抑制、UVB照射或病毒感染的条件下，分别仅有20%、5%和0%的小鼠出现病理性增生，肿瘤发生率显著降低。BRAF抑制剂与UVB的联合暴露促进了病毒的有效感染，表现为高水平的MmuPV1基因组拷贝数、E1^E4剪接转录本，以及丰富的E6/E7癌基因mRNA和病毒衣壳蛋白。BRAF抑制（而非病毒感染或UVB照射）激活了ERK1/2，而UVB可诱导的γH2AX表达在BRAF抑制剂作用下保持不变。这些结果为BRAF抑制与UVB照射在体内协同促进MmuPV1诱导的皮肤肿瘤发展提供了实验证据，表明乳头瘤病毒感染可能通过替代途径参与BRAF抑制剂相关的皮肤肿瘤发生。
肿瘤(癌症)患者之家