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Gastrointestinal stromal tumours: origin and molecular oncology

Nature Reviews Cancer volume 11, pages 865–878 (2011)Cite this article

Subjects

Key Points

  • Gastrointestinal stromal tumours (GISTs) are a family of tumours thought to arise from the interstitial cells of Cajal in the gastrointestinal tract. Recently, the putative stem and progenitor cells for GISTs have been identified.

  • Most GISTs have oncogenic mutations in either KIT or platelet-derived growth factor receptor-α (PDGFRA), and targeting these mutant proteins with kinase inhibitors is effective in patients with advanced disease. There is substantial evidence that these mutations are pathogenetic for the initiation of GISTs.

  • GISTs lacking KIT or PDGFRA mutations (known as wild-type GISTs) are a heterogeneous group, of which some have alterations in BRAF, RAS or in the genes of the succinate dehydrogenase complex.

  • Classification of GISTs on the basis of molecular defects is relevant to the clinical management of patients. Notably, the response to kinase inhibitor therapy is influenced by the primary kinase genotype.

  • Secondary mutations in KIT or PDGFRA eventually lead to drug resistance in most patients.

  • A subpopulation of GIST cells with stem cell-like characteristics may be less sensitive to kinase inhibitors, providing the seed for drug resistance.

Abstract

Gastrointestinal stromal tumours (GISTs) are a paradigm for the development of personalized treatment for cancer patients. The nearly simultaneous discovery of a biomarker that is reflective of their origin and the presence of gain-of-function kinase mutations in these tumours set the stage for more accurate diagnosis and the development of kinase inhibitor therapy. Subsequent studies of genotype and phenotype have led to a molecular classification of GIST and to treatment optimization on the basis of molecular subtype. The study of drug-resistant tumours has advanced our understanding of kinase biology, enabling the development of novel kinase inhibitors. Further improvements in GIST treatment may require targeting GIST stem cell populations and/or additional genomic events.

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Figure 1: KIT and PDGFRA structure and mutations.
Figure 2: Oncogenic signalling in KIT and PDGFRA-mutant GISTs.
Figure 3: Oncogenic signalling in wild-type GISTs.
Figure 4: Secondary mutations in KIT and their drug sensitivities.

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Acknowledgements

The authors wish to acknowledge all of the members of their laboratories for their continuing efforts on gastrointestinal stromal tumour (GIST) research. Some of the work referenced in this article was supported by generous donations from the GIST Cancer Research Fund and the BP Lester Foundation, and by grant support from the LifeRaft Group. In addition, M.C.H. received research grant funding from the Department of Veterans Affairs (Merit Review Award).

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  1. Division of Haematology & Oncology, and Department of Pathology, Knight Cancer Institute, Portland VA Medical Center and Oregon Health & Science University, Portland, 97239, Oregon, USA

    Christopher L. Corless, Christine M. Barnett & Michael C. Heinrich

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Correspondence to Michael C. Heinrich.

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C.L.C. declares honoraria or consulting fees from Novartis and Pfizer, research support from Novartis and clinical trial contracts with Novartis, Synta and Astex. M.C.H. declares equity interest in Molecular MD, research support from Novartis, AROG, Imclone and Ariad, and clinical trials contracts with Novartis, Pfizer, Astex, Synta and AROG. M.C.H. competing interests are managed by Conflict of Interest management committees at OHSU and PVAMC.

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Type III receptor tyrosine kinase

A family of kinases sharing a structure that consists of five extracellular immunoglobulin-like domains, a transmembrane domain and a split kinase domain.

Dysphagia

Difficulty swallowing.

Myenteric

Referring to the gastrointestinal tract.

Mesentery

The membranous support for blood vessels serving the gastrointestinal tract.

Omentum

A fatty membrane attached to the stomach and covering the anterior abdomen.

Cross-over

Switching from one arm of a trial to the other.

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Corless, C., Barnett, C. & Heinrich, M. Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev Cancer 11, 865–878 (2011). https://doi.org/10.1038/nrc3143

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