Emerging BRAF inhibitors for melanoma.
BACKGROUND
The clinical activity of BRAF inhibitor (BRAF-I) therapy is a major breakthrough in the treatment of metastatic melanoma carrying BRAF mutations. However, the therapeutic efficacy of BRAF-I therapy is limited due to the onset of intrinsic and acquired drug resistance.


METHODS
The role of wild-type BRAF in melanocytes and of the mutated BRAF in the pathogenesis of melanoma is described in this article. The results obtained with BRAF-I in patients with mutated BRAF are reviewed. The mechanisms driving the intrinsic and acquired BRAF-I resistance, the development of combinatorial strategies designed to overcome them and their potential limitations are discussed. Lastly, the many questions that have to be addressed to optimize therapy with BRAF-I are listed.


CONCLUSIONS
Melanoma is an aggressive form of skin cancer characterized by poor prognosis and high mortality. The discovery of BRAF mutations which drive melanoma tumorigenesis and the development of agents which selectively inhibit mutant-activated BRAF represent a major breakthrough in the treatment of metastatic melanoma. However, the development of drug resistance underlies the need of more effective and individualized combinatorial treatments to counteract the multiple escape mechanisms utilized by BRAF-mutant melanoma. Although combinatorial strategies using agents which target different protumorigenic signaling pathway components have been shown to increase the clinical efficacy of BRAF-I, novel strategies which utilize different antitumor mechanisms are needed.
Massachusetts General Hospital, Harvard Medical School, Department of Surgery , 55 Fruit Street, Boston, MA 02114 , USA +1 617 726 6087 ; sferrone@partners.org.
Francesco
F
Sabbatino
Yangyang
Y
Wang
Xinhui
X
Wang
Soldano
S
Ferrone
Cristina R
CR
Ferrone
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D055808:Drug Discovery; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D058990:Molecular Targeted Therapy; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics
D000970:Antineoplastic Agents; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf