Table 2.

Clinically validated mechanisms of resistance to RAF inhibitors in melanoma patients

ReferenceTreatmentResistance mechanisms
Johannessen and colleagues (34)VemurafenibIncreased COT expression
Nazarian andVemurafenibPDGFβ upregulation
colleagues (35)NRAS mutation
Poulikakos and colleagues (25)VemurafenibAberrantly spliced BRAF
Wagle and colleagues (36)VemurafenibMEK1 mutation
Villaneuva and colleagues (37)VemurafenibIncreased IGF1R expression
Shi and colleaguesVemurafenibBRAF amplification
(38)BRAF truncation
NRAS mutation
Increased RTK expression
Straussman and colleagues (39)Vemurafenib or dabrafenib + trametinibStromal HGF secretion
Whittaker and colleagues (40)VemurafenibNF1 loss
Trunzer andVemurafenibNRAS mutation
colleagues (41)MEK1 mutation
Van Allen andVemurafenib orNRAS mutation
colleagues (42)dabrafenibBRAF amplification
MEK1 mutation
MEK2 mutation
MITF amplification
Shi and colleaguesVemurafenib orNRAS mutation
(43)dabrafenibBRAF amplification
Aberrantly spliced BRAF
MEK1 mutation
KRAS mutation
Rizos and colleaguesVemurafenib orNRAS mutation
and Johnson anddabrafenibAberrantly spliced BRAF
colleagues (44, 45)BRAF amplification
MEK1 mutation
MEK2 mutation
KRAS mutation
Increased IGF1R expression
AKT1 mutation
PIK3CA mutation
PTEN loss
DUSP4 deletion
AKT3 mutation
MITF amplification
PDGFR upregulation
Sun and colleagues (46)Vemurafenib or dabrafenib or trametinibEGFR expression
Wagle and colleaguesDabrafenib +MEK2 mutation
(47)trametinibBRAF amplification
Aberrantly spliced BRAF
Villanueva and colleagues (48)Trametinib followed by dabrafenibMEK2 mutation plus BRAF amplification