Range of KIT mutations in gastrointestinal stromal tumors (GIST)

KIT is a type III receptor tyrosine kinase that is comprised of extracellular ligand-binding and dimerization domains, a transmembrane sequence, as well as an intracellular juxtamembrane domain and kinase domain, which is split by an 80 amino acid insert. Mutations in exon 11 of KIT, which encode the juxtamembrane domain and are seen in approximately 70% of GISTs, relieve its autoinhibitory function and lead to constitutive, ligand-independent activation of the receptor. Mutations in the dimerization domain, encoded by exon 9 (approximately 12% of GISTs), allow receptor dimerization in the absence of ligand and likewise lead to activation of the kinase. Mutations in the kinase domain (exons 13/14, ATP-binding, phosphotransferase region; exons 17/18, activation loop) are rare in primary, imatinib-naïve GISTs. However, because they favor the active conformation of the kinase, leading to impaired binding of imatinib, they comprise the most prominent imatinib resistance mechanism. A comparison of the relative effectiveness of IM, SU, and REGO in GIST with the most frequent KIT secondary mutations is shown on the right.