title: Paradoxical oncogenesis--the long-term effects of BRAF inhibition in melanoma.
abstract: The clinical benefits of BRAF inhibition in patients with advanced-stage BRAF-mutant melanoma are now well established. Although the emergence of cutaneous squamous-cell carcinomas (SCCs) and secondary melanomas in patients on BRAF-inhibitor therapy have been well described, reports are emerging of additional secondary premalignant and malignant events, including RAS-mutant leukaemia, the metastatic recurrence of RAS-mutant colorectal cancer and the development of gastric and colonic polyps. In most cases, paradoxical MAPK activation--resulting from the BRAF-inhibitor-mediated homodimerization and heterodimerization of nonmutant RAF isoforms--seems to underlie the development of these secondary tumours. Although evidence supports that therapy with the simultaneous administration of BRAF and MEK inhibitors abrogates the onset of treatment-induced SCCs, whether combination treatment will limit the emergence of all BRAF-inhibitor-driven pathologies is unclear. In this Review, we describe the clinical and mechanistic manifestations of secondary cancers that have thus far been observed to arise as a consequence of BRAF inhibition. We discuss the concept of pre-existing populations of partly transformed cells with malignant potential that might be present in various organ systems, and the rationale for novel therapeutic strategies for the management of BRAF-inhibitor-induced neoplasia.
authors.affiliation: Department of Cutaneous Oncology, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.
authors.forename: Geoffrey T
authors.initials: GT
authors.lastname: Gibney
authors.forename: Jane L
authors.initials: JL
authors.lastname: Messina
authors.forename: Inna V
authors.initials: IV
authors.lastname: Fedorenko
authors.forename: Vernon K
authors.initials: VK
authors.lastname: Sondak
authors.forename: Keiran S M
authors.initials: KS
authors.lastname: Smalley
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects*; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf