Molecular pathobiology of gastrointestinal stromal sarcomas.
Gastrointestinal stromal tumors (GISTs) form an interesting group of sarcomas whose unique pathobiology provides a model of how molecularly targeted therapeutics can have a major impact on patient welfare. Approximately 85% of GISTs are driven by oncogenic mutations in either of two receptor tyrosine kinases: KIT or platelet-derived growth factor receptor alpha. We review the pivotal relationship between specific mutations in these kinase genes, the origin and pathologic spectrum of GISTs, and the response of these tumors to treatment with kinase inhibitors such as imatinib and sunitinib. Mechanisms of resistance to kinase inhibitor therapy are discussed, and targets for the next generation of therapeutics are considered. The rapid evolution in our understanding of GISTs, which stems directly from the close alliance of basic and clinical researchers in the field, illustrates the growing role of the molecular classification of solid tumors in the development of modern oncological treatments.
Corless
Christopher L
CL
Department of Pathology, Oregon Health & Science University Cancer Institute, Portland, OR 97239, USA corlessc@ohsu.edu
Heinrich
Michael C
MC
D001549:Benzamides; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000627:therapeutic use; D009154:Mutation; D010879:Piperazines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D012509:Sarcoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D000077210:Sunitinib
D001549:Benzamides; 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; D000077210:Sunitinib