Molecular pathobiology of gastrointestinal stromal sarcomas

Annu Rev Pathol. 2008;3:557-86. doi: 10.1146/annurev.pathmechdis.3.121806.151538.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Benzamides
  • Gastrointestinal Stromal Tumors / drug therapy
  • Gastrointestinal Stromal Tumors / genetics
  • Gastrointestinal Stromal Tumors / pathology*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Imatinib Mesylate
  • Indoles / therapeutic use
  • Mutation
  • Piperazines / therapeutic use
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins c-kit / genetics
  • Proto-Oncogene Proteins c-kit / metabolism
  • Pyrimidines / therapeutic use
  • Pyrroles / therapeutic use
  • Receptor, Platelet-Derived Growth Factor alpha / genetics
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism
  • Sarcoma / drug therapy
  • Sarcoma / genetics
  • Sarcoma / pathology*
  • Sunitinib


  • Benzamides
  • Indoles
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Pyrroles
  • Imatinib Mesylate
  • Proto-Oncogene Proteins c-kit
  • Receptor, Platelet-Derived Growth Factor alpha
  • Sunitinib