[Therapeutic targets in gastrointestinal stromal tumors].
Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors in the gastrointestinal tract, metastasize in up to 50 % of cases and are resistant to conventional radio- and chemotherapy. They are characterized by the expression of the type III receptor tyrosine kinase KIT which is the most important diagnostic immunohistochemical feature. Genomically, the majority of GISTs carry heterozygous mutations in the KIT or the PDGF receptor alpha gene leading to an autophosphorylation of the respective receptor protein. The evaluation of the mutational status allows the subdivision of GISTs into different prognostic sub-groups. For example, GISTs carrying an activating mutation in PDGF receptor alpha are most often located in the stomach and seem to have a better prognosis than GISTs with a KIT mutation. Specific mutational subtypes of KIT mutations in exon 11 (esp. proximal deletions of codons tryptophane-557 and lysine-558) have a significantly higher metastatic risk than GISTs with KIT mutations located in the distal part of exon 11 (esp. insertions/duplications). GISTs in the small bowel most often carry KIT exon 9 mutations and have a worse prognosis than GISTs with exon 11 mutations. Mutational subtype in KIT or PDGF receptor alpha not only influences the biological behavior of GISTs but also their response to treatment with imatinib, a tyrosine kinase inhibitor also inhibiting ARG, PDGF receptor beta and BCR-ABL. KIT exon 11 mutated tumors show response rates of up to 80 % of cases whereas KIT exon 9 mutated GISTs respond in less then 50 %. GISTs without detectable KIT mutation in these both exons often are resistant to imatinib. The development of secondary resistance to imatinib in GIST patients occurs in up to 40% of cases and is partly due to secondary KIT mutations occuring additionally to the primary mutation. Actually, several studies evaluate the efficacy of alternative small molecules such as SU 11248, RAD001 and AMG706 inhibiting signal transduction pathways downstream of KIT and PDGF receptor alpha. In summary, mutational status in KIT or PDGF receptor alpha of GISTs is relevant for prognosis, for response to treatment and for further insights into mechanisms of treatment failure.
Wardelmann
E
E
Institut für Pathologie, Universitätsklinikum Bonn.
Schildhaus
H-U
HU
Merkelbach-Bruse
S
S
Büttner
R
R
D004791:Enzyme Inhibitors / Q000627:therapeutic use; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D006801:Humans; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics
D004791:Enzyme Inhibitors; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha