Vemurafenib cooperates with HPV to promote initiation of cutaneous tumors

Area of Science:

• Oncology
• Dermatology
• Virology

Background:

• RAF inhibitors, such as vemurafenib, are associated with cutaneous squamous cell carcinoma (cSCC) and keratoacanthoma development in 18-30% of patients.
• RAF inhibitors activate the MAPK pathway, potentially promoting RAS-mutated cell growth, which is implicated in up to 60% of cSCC/keratoacanthoma lesions.

Purpose of the Study:

• To investigate the role of human papilloma virus (HPV) in vemurafenib-induced skin tumorigenesis.
• To determine if HPV infection cooperates with RAF inhibitors to promote cSCC development.

Main Methods:

• Tumor samples from vemurafenib-treated patients were tested for HPV DNA.
• A transgenic murine model (K14-HPV16 mice) was used to assess the effect of vemurafenib on HPV-infected tissues.
• MAPK pathway markers and cSCC incidence were evaluated in the murine model.

Main Results:

• HPV DNA was detected in 13% of cSCCs from vemurafenib-treated patients.
• Vemurafenib treatment significantly increased cSCC incidence in HPV-infected mice (from 22% to 70%).
• 55% of cSCCs in treated mice had wild-type Ras genotype, indicating HPV's role independent of RAS mutations.

Conclusions:

• Human papilloma virus (HPV) cooperates with vemurafenib to promote cutaneous squamous cell carcinoma (cSCC) development.
• This cooperation occurs irrespective of RAS mutational status.
• Findings suggest a novel mechanism for drug-induced skin tumorigenesis involving viral co-factors.