Background: It is well recognized that cutaneous reactions such as verrucal keratosis (VK) and squamous cell carcinoma (cuSCC) are one of the most frequent adverse events associated with the BRAF inhibitors (BRAFi), vemurafenib and dabrafenib. These agents are used in the treatment of V600 mutant melanoma and induce hyperproliferation of wild type BRAF keratinocytes. Here we report the molecular interplay involved in the formation of BRAFi induced hyperproliferative keratinocytic lesions, cuSCC and VK, seen in patients taking BRAFi.
Methods: Twenty tissue samples of cuSCC and VK were collected from patients treated with BRAFi for stage IV melanoma. Immunohistochemistry analysis was performed using a panel consisted of components of the MAPK pathway (p-BRAF, p-CRAF, p-MEK, p-ERK), Pi3K-AKT pathway (p-AKT3, Pi3K), cell cycle control molecule cyclin D, markers of cellular proliferation (Ki67, keratin 6), keratin 10 and oncogenic protein (p53).
Results: When antibody expression of cuSCCs was compared to VK, a significantly higher expression of p-ERK was found in basal and suprabasal layer of cuSCC compared to VK. Comparison of VK and cuSCC to normal surrounding skin showed statistically significant (p<0.05) variation in antibody stain and location. In particular it was noted that Ki67 was up regulated in the basal and suprabasal layer as well as p-ERK and Keratin 6 which were up regulated in the upper layers of the disease skin (stratum spinosum). Cyclin D had higher expression in disease skin in the basal layer than in normal skin, whereas Keratin 10, marker of cellular differentiation, had a lower expression in the suprabasal layer in comparison to normal skin.
Conclusions: Our results indicated that the MAPK pathway is upregulated in patients taking BRAFi. The immunohistological differences between VK and cuSCC were minimal and suggestive of a progression from normal epidermis, to VK to cuSCC.