KIT mutations in GIST.
Most gastrointestinal stromal tumors (GISTs) contain oncogenic KIT or PDGFRA receptor tyrosine kinase mutations. These rare neoplasms are remarkably sensitive to the KIT and PDGFRA kinase inhibitors imatinib (also known as Gleevec) and sunitinib (Sutent), which have recently been approved as the standard therapeutic courses for patients with inoperable GIST. However, most GIST patients eventually develop clinical resistance to imatinib and sunitinib. Imatinib and sunitinib resistance generally result from secondary mutations in the KIT and/or PDGFRA kinase domains. Preclinical studies suggest that imatinib and sunitinib resistant mutations can be treated using more potent kinase inhibitors, such as nilotinib, which inactivate the mutant kinase proteins. Alternately, the mutant kinase proteins can be targeted using HSP90 inhibitors, which result in degradation of activated KIT and/or PDGFRA, or using KIT transcriptional repressors, such as flavopiridol.
Fletcher
Jonathan A
JA
Brigham and Women's Hospital, 75 Francis Street, Thorn 5, Boston, MA 02115, USA. jfletcher@partners.org
Rubin
Brian P
BP
D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use; D001549:Benzamides; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000378:metabolism / Q000627:therapeutic use; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D010879:Piperazines / Q000378:metabolism / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000627:therapeutic use; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D011743:Pyrimidines / Q000378:metabolism / Q000627:therapeutic use; D011758:Pyrroles / Q000378:metabolism / Q000627:therapeutic use; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D000077210:Sunitinib
D000970:Antineoplastic Agents; D001549:Benzamides; D018841:HSP90 Heat-Shock Proteins; D007211:Indoles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; C498826:nilotinib; D000077210:Sunitinib