BRAF Inhibition and UVB Light Synergistically Promote Mus musculus Papillomavirus 1-Induced Skin Tumorigenesis

Area of Science:

• Oncology
• Dermatology
• Virology

Background:

• BRAF inhibitors (BRAFis) are used in targeted cancer therapy.
• BRAFis can paradoxically activate the MAPK pathway, leading to keratinocytic skin tumors.
• The role of cutaneous papillomavirus infection in BRAFi-associated skin carcinogenesis is unclear.

Purpose of the Study:

• To investigate the impact of BRAF inhibitors and UVB exposure on papillomavirus-induced skin tumorigenesis.
• To determine if BRAF inhibition and UVB light synergize to promote skin tumor development in a mouse model of papillomavirus infection.

Main Methods:

• Utilized the Mus musculus papillomavirus 1 (MmuPV1) skin infection model in immunocompetent FVB/NCrl mice.
• Administered systemic BRAF inhibition and UVB exposure to MmuPV1-infected mice.
• Assessed tumor development, viral load (MmuPV1 genome copies, spliced transcripts, oncogene mRNA, capsid proteins), and molecular markers (ERK1/2, γH2AX).

Main Results:

• Combined BRAF inhibition and UVB light induced skin tumors in 62% of MmuPV1-infected mice.
• Significantly fewer tumors were observed with BRAF inhibition alone (20%), UVB irradiation alone (5%), or viral infection alone (0%).
• Combinatory exposure favored productive viral infection and activated ERK1/2, while UVB induced γH2AX.

Conclusions:

• BRAF inhibition and UVB irradiation synergistically promote MmuPV1-induced skin tumor development in vivo.
• This suggests an alternative pathway where papillomavirus infection contributes to BRAFi-associated skin tumorigenesis.
• Findings highlight the complex interplay between targeted therapies, environmental factors, and viral infections in skin carcinogenesis.