Targeting Activated KIT Signaling for

See accompanying articles doi: 10.1200/JCO.2013.50.4662 and doi: 10.1200/JCO.2013.50.3227 Melanomas are composed of several biologically distinct categories of neoplasms that differ in their clinical and histologic presentations, cell of origin, ageofonset, ethnic variation,pathogenetic roleofultraviolet radiation, predisposing germline alterations, typeof genomic instabil-ity,patternofmetastasis, andpatternsof somaticmutation.1The latter contain a set of recurrent gain-of-function mutations in the genes NRAS,BRAF,KIT,GNAQ, andGNA11 that tend to occur in amutu-ally exclusive pattern early during progression. KIT is a receptor ty-rosine kinase that binds to stem-cell factor (SCF), activating a series of downstreameffector pathways (Fig 1). KIT is of critical importance in melanocyte development. It is expressed in earlymelanoblasts, which receive positional cues from SCF-expressing epithelia, while they mi-grate dorsoventrally through the superficial mesenchyme to reach their destination in the epidermis and hair follicles. Loss-of-functio