title: RAF signaling in neuroendocrine neoplasms: from bench to bedside.
abstract: Neuroendocrine neoplasms are a low-incidence and heterogeneous group of malignancies. In the advanced stage, several therapeutic options can be discussed, including molecular-targeted agents, but biological predicting factors are lacking. A number of molecular targets have been studied over the last decade leading to several phase II studies; however, very few agents progressed to phase III clinical trials. The RAF family of proteins belongs to the mitogen-activated protein kinase (MAPK) pathway, that has a role in several types of cancers, particularly related to BRAF mutations. Indeed BRAF inhibitors have been reported as being effective, mainly in melanoma. However, in neuroendocrine neoplasms BRAF mutations are extremely rare and RAF-1 activation has been reported to inhibit tumor growth in a pre-clinical setting. Therefore, in this field, RAF-1 activators rather than BRAF inhibitors should be clinically investigated. This article reviews the basic science as well as clinical data of RAF signaling in advanced neuroendocrine neoplasms with special emphasis on the potential role of both RAF activators and inhibitors.
authors.affiliation: Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, Milan, Italy. Electronic address: nicola.fazio@ieo.it.
authors.forename: Nicola
authors.initials: N
authors.lastname: Fazio
authors.affiliation: Clinical Oncology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Rahman
authors.affiliation: Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Spada
authors.affiliation: Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, Milan, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Galdy
authors.affiliation: Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
authors.forename: Sara
authors.initials: S
authors.lastname: De Dosso
authors.affiliation: Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Capdevila
authors.affiliation: Department of Pathology and Diagnostics, ARC-NET Research Center, University of Verona, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
mesh_terms: D000818:Animals; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D006801:Humans; D020935:MAP Kinase Signaling System; D058990:Molecular Targeted Therapy; D018358:Neuroendocrine Tumors / Q000188:drug therapy / Q000201:enzymology*; D048490:raf Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D048490:raf Kinases
keywords: BRAF; Cell signaling; MAPK; Molecular targeted therapy; NET; Neuroendocrine neoplasms; Neuroendocrine tumors; RAF; RAF-1