Induction of Cutaneous Squamous Cell Carcinomas by RAF Inhibitors: Cause for Concern?

See accompanying article on page 316 Approximately 50 % of melanomas harbor a mutation in theBRAF gene.1 Vemurafenib (formerly PLX4032) is an adenosine triphosphate– competitive inhibitor of RAF kinases that has shown profound activity in patients with advanced melanoma.2 A notable property of vemurafenib and other selective RAF inhibitors is that they inhibit RAF activation of extracellular signal–regulated kinase (ERK) only in tumors expressing mutantBRAF (Fig 1A). InBRAFwild-type tumors as well as normal cells, they activate this pathway (Fig 1B).3-6 This paradoxical activation of RAF signaling by the RAF inhibitor likely accounts for its unique toxicity profile. Approximately one third of patients treated with vemurafenib develop a keratosis pilaris–like rash.2 This rash is histologically characterized by perifollicular hyper-plasia and is often accompanied by hyperkeratosis of the palms and soles (palma-plantar dysesthesia) and/or the development