The Many Faces of the Paradoxical Response to BRAF Inhibitors

Paradoxical oncogenesis was observed as early as one decade ago with pan-RAF inhibitors. The list of proliferative disorders has become even longer with the advent of selective BRAF inhibitors and includes not only skin premalignancies and malignancies, but also various epithelial, melanocytic, and vascular benign proliferations and, even now, non-skin malignancies. From the experimental side, the findings from an increasing number of important studies support a widely accepted mechanistic model of paradoxical oncogenesis. In the present review, we discuss the extent to which this model can be used to understand the variety of BRAF inhibitor-induced proliferative disorders. We also discuss a wider clinical and mechanistic definition of the paradoxical response to BRAF inhibitors, its links to the adaptive resistance to BRAF inhibition in melanoma, and its consequences for upcoming therapeutic developments.