BRAF inhibitors: two edged sword

Somatic mutations in BRAF occur in two thirds of cutaneous melanomas, leading to the activation of the RAF-MEK-ERK signalling pathway. Preclinical studies of BRAF mutations showed that inhibition of BRAF led to melanoma cell proliferation inhibition and apoptosis induction in vitro and blockade of melanoma xenograft growth in vivo. Clinical studies of BRAF inhibitors in BRAF-mutated metastatic melanoma revealed superior outcomes in patients treated with these agents when compared to cytotoxic chemotherapy. As a result, BRAF inhibitors are currently licenced by the regulatory authorities in the United States and Europe in BRAFmutated metastatic melanoma. BRAF inhibitors paradoxically cause squamous cell carcinoma in melanoma patients treated with these agents. In this review we will discuss the mechanisms and the importance of this phenomenon. It is an example of the challenges that accompany the hope that targeted therapy brings to cancer patients as well as to their treating physicians.