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Ref Type Journal Article
PMID (25653539)
Authors Spagnolo F, Ghiorzo P, Orgiano L, Pastorino L, Picasso V, Tornari E, Ottaviano V, Queirolo P
Title BRAF-mutant melanoma: treatment approaches, resistance mechanisms, and diagnostic strategies.
Journal OncoTargets and therapy
Vol 8
Issue
Date 2015
URL
Abstract Text BRAF inhibitors vemurafenib and dabrafenib achieved improved overall survival over chemotherapy and have been approved for the treatment of BRAF-mutated metastatic melanoma. More recently, the combination of BRAF inhibitor dabrafenib with MEK inhibitor trametinib has shown improved progression-free survival, compared to dabrafenib monotherapy, in a Phase II study and has received approval by the US Food and Drug Administration. However, even when treated with the combination, most patients develop mechanisms of acquired resistance, and some of them do not achieve tumor regression at all, because of intrinsic resistance to therapy. Along with the development of BRAF inhibitors, immunotherapy made an important step forward: ipilimumab, an anti-CTLA-4 monoclonal antibody, was approved for the treatment of metastatic melanoma; anti-PD-1 agents achieved promising results in Phase I/II trials, and data from Phase III studies will be ready soon. The availability of such drugs, which are effective regardless of BRAF status, has made the therapeutic approach more complex, as first-line treatment with BRAF inhibitors may not be the best choice for all BRAF-mutated patients. The aim of this paper is to review the systemic therapeutic options available today for patients affected by BRAF V600-mutated metastatic melanoma, as well as to summarize the mechanisms of resistance to BRAF inhibitors and discuss the possible strategies to overcome them. Moreover, since the molecular analysis of tumor specimens is now a pivotal and decisional factor in the treatment strategy of metastatic melanoma patients, the advances in the molecular detection techniques for the BRAF V600 mutation will be reported.

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Molecular Profile Treatment Approach
BRAF V600dup MEK inhibitor (Pan)
BRAF T599dup MEK inhibitor (Pan)
BRAF F247L MEK inhibitor (Pan)
BRAF A598_T599insARC MEK inhibitor (Pan)
BRAF L597Q MEK inhibitor (Pan)
BRAF G596R MEK inhibitor (Pan)
BRAF D287H MEK inhibitor (Pan)
BRAF V600X MEK1 Inhibitor
BRAF V600E MEK inhibitor (Pan)
BRAF V600L MEK inhibitor (Pan)
BRAF K601E MEK inhibitor (Pan)
BRAF D594E MEK inhibitor (Pan)
BRAF G464E MEK inhibitor (Pan)
BRAF L597S MEK inhibitor (Pan)
BRAF K499E MEK inhibitor (Pan)
BRAF V600M RAF Inhibitor (Pan)
BRAF V600R RAF Inhibitor (Pan)
BRAF V600G RAF Inhibitor (Pan)
BRAF V600E/K MEK inhibitor (Pan)
BRAF L485F MEK inhibitor (Pan)
BRAF V600R MEK inhibitor (Pan)
BRAF V600D RAF Inhibitor (Pan)
BRAF T599R MEK inhibitor (Pan)
BRAF K601I MEK inhibitor (Pan)
BRAF G464V MEK inhibitor (Pan)
BRAF L597R MEK inhibitor (Pan)
BRAF L485_P490del MEK inhibitor (Pan)
BRAF L485_P490delinsY MEK inhibitor (Pan)
BRAF L485_P490delinsF MEK inhibitor (Pan)
BRAF V600E RAF Inhibitor (Pan)
BRAF V600X BRAF Inhibitor
BRAF I463S MEK inhibitor (Pan)
BRAF D594H MEK inhibitor (Pan)
BRAF G469R MEK inhibitor (Pan)
BRAF G464R MEK inhibitor (Pan)
BRAF G466V MEK inhibitor (Pan)
BRAF G469V MEK inhibitor (Pan)
BRAF V600G MEK inhibitor (Pan)
BRAF D594N MEK inhibitor (Pan)
BRAF A598_T599insV MEK inhibitor (Pan)
BRAF act mut MEK inhibitor (Pan)
BRAF G469L MEK inhibitor (Pan)
BRAF V504_R506dup MEK inhibitor (Pan)
BRAF D594Y MEK inhibitor (Pan)
BRAF S467A MEK inhibitor (Pan)
BRAF N486_P490del MEK inhibitor (Pan)
BRAF V600D MEK inhibitor (Pan)
BRAF L485_Q494del MEK inhibitor (Pan)
BRAF K601T MEK inhibitor (Pan)
BRAF E586K MEK inhibitor (Pan)
BRAF G596D MEK inhibitor (Pan)
BRAF L597V MEK inhibitor (Pan)
BRAF V487_P492delinsA MEK inhibitor (Pan)
BRAF F468C MEK inhibitor (Pan)
BRAF V600M MEK inhibitor (Pan)
BRAF L597P MEK inhibitor (Pan)
BRAF P490_Q494del MEK inhibitor (Pan)
BRAF T599_V600insTT MEK inhibitor (Pan)
BRAF A598V MEK inhibitor (Pan)
BRAF G469A MEK inhibitor (Pan)
BRAF T599_V600insETT MEK inhibitor (Pan)
BRAF T488_P492del MEK inhibitor (Pan)
BRAF G466R MEK inhibitor (Pan)
BRAF V600Q RAF Inhibitor (Pan)
BRAF V600_K601delinsE MEK inhibitor (Pan)
BRAF F595L MEK inhibitor (Pan)
BRAF T599_V600insEAT MEK inhibitor (Pan)
BRAF G469del MEK inhibitor (Pan)
BRAF Q257R MEK inhibitor (Pan)
BRAF A728V MEK inhibitor (Pan)
BRAF R347* MEK inhibitor (Pan)
BRAF V471F MEK inhibitor (Pan)
BRAF G469S MEK inhibitor (Pan)
BRAF V600L RAF Inhibitor (Pan)
BRAF V600E/K RAF Inhibitor (Pan)
BRAF D594_T599dup MEK inhibitor (Pan)
BRAF V600X MEK2 Inhibitor
BRAF D594A MEK inhibitor (Pan)
BRAF V600X MEK inhibitor (Pan)
BRAF V600K RAF Inhibitor (Pan)
BRAF K601N MEK inhibitor (Pan)
BRAF N486_T491delinsK MEK inhibitor (Pan)
BRAF G596C MEK inhibitor (Pan)
BRAF K601Q MEK inhibitor (Pan)
BRAF G596V MEK inhibitor (Pan)
BRAF V600X RAF Inhibitor (Pan)
BRAF T599I MEK inhibitor (Pan)
BRAF V600Q MEK inhibitor (Pan)
BRAF T488_Q493delinsK MEK inhibitor (Pan)
BRAF L505H MEK inhibitor (Pan)
BRAF V600delinsYM MEK inhibitor (Pan)
BRAF V600K MEK inhibitor (Pan)
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References