key papersKey paper
PDGFRA activating mutations in gastrointestinal stromal tumours
This study found that most gastrointestinal stromal tumours without KIT mutations instead carry activating mutations in the related receptor PDGFRA, including the D842V mutation that resists imatinib, completing the genetic definition of the disease.
Overview
Mutation analysis of KIT-wild-type gastrointestinal stromal tumours identifying activating PDGFRA mutations in about a third, mutually exclusive with KIT mutations, with the mutant receptors showing constitutive activation and, for D842V, resistance to imatinib in vitro, while other PDGFRA mutants were sensitive.
Basic scienceChanged practice
Authors
Heinrich MC, Corless CL, Duensing A, et al.
Published
Science, 2003
Findings
- PDGFRA mutations in about 35 percent of KIT wild-type GISTs.
- D842V mutant resistant to imatinib; other PDGFRA mutants sensitive.
What it means
PDGFRA testing is part of standard GIST genotyping, and the imatinib resistance of D842V predicted here led to the development of avapritinib.
Caveats
- Discovery study; clinical resistance of D842V was confirmed in later trials.