[Activating mutations in receptor tyrosine kinases with relevance for treatment of gastrointestinal stromal tumors].

Aims: Receptor tyrosine kinases have been shown to be a challenging target for the treatment of hematologic diseases and solid tumors. One very effective tyrosine kinase inhibitor is imatinib mesylate inhibiting the KIT receptor tyrosine kinase in gastrointestinal stromal tumors (GISTs) which often carry activating mutations in the KIT gene. Our own observations show that the location of the underlying mutations influence the response to treatment with imatinib.

Methods: In Bonn, nearly 1000 GISTs have been characterized molecularily before and/or under treatment with tyrosine kinase inhibitors. Tumor-DNA was extracted from paraffine-embedded material, amplified in all known hot spots of KIT (exons 9, 11, 13, 14, 17) and PDGFRcx (exons 12, 14, 18) and sequenced directly.

Results: The best response to treatment with imatinib is achieved in GISTs with an underlying KIT mutation in exon 11 encoding the juxtamembranous domain. Exon 9 mutated GISTs respond in only half of the cases. GISTs with mutations in the tyrosine kinase domain 1 or 2 are very rare (less than 1%) and are thought to be resistant. PDGFRalpha-mutated GISTs are resistant when carrying the most common point mutation D842V (exon 18) and may respond when deletions occur in exon 18. Low response rates are achieved in tumors without detectable mutation. Under treatment, secondary KIT mutations may occur leading to resistance to treatment.

Conclusions: The molecular status of GISTs plays a central role for treatment response. Its evaluation will be mandatory in the future at least in tumors with intermediate or high risk criteria.