Beneficial effects of RAF inhibitor in mutant BRAF splice variant-expressing melanoma.

Resistance to RAF inhibitors such as vemurafenib and dabrafenib is a major clinical problem in the treatment of melanoma.PatientswithmutantBRAFmelanomathatprogressonRAFinhibitorshavelimitedtreatmentoptions, and drug removal from resistant tumors may elicit multiple effects. A frequent mechanism of resistance to RAF inhibitors is caused by expression of mutant BRAF splice variants. RAF inhibitor–resistant cell lines, generated in vivo,weretestedastowhetherornotmutantBRAFsplicevariantsconfera fitnessadvantageinthepresenceofRAF inhibitor. Critically, cells expressing distinct mutant BRAF splice variants grow more efficientlyin vitroand in vivo inthepresenceofthevemurafenibanalog, PLX4720,comparedwithintheabsence ofinhibitor.PLX4720-treated BRAF splice variant–expressing cells exhibited levels of phospho-extracellular signal–regulated kinase (ERK)1/2 comparabletountreatedparentalcells.Inaddition,areductioninphospho-ERK1/2levelsfollowingtreatmentwith the MEK inhibitor, trametinib (GSK1120212) phenocopied the fitness benefit provided by PLX4720. These data indicate that mutant BRAF splice variant–expressing melanoma cells are benefited by defined concentrations of RAF inhibitors. Implications: This study provides evidence that RAF inhibitor–resistant melanoma cells benefit from continued therapy. Mol Cancer Res; 1–8. � 2014 AACR.