Predictive Biomarkers and Personalized Medicine KRAS and BRAF Mutations Predict Primary Resistance to Imatinib in Gastrointestinal Stromal Tumors

Purpose:Gastrointestinal stromal tumors (GIST) are characterized by gain-of-functionmutations inKIT/ PDGFRA genes leading to a constitutive receptor activation which is well counteracted by imatinib. However, cases in which imatinib as first-line treatment has no effects are reported (primary resistance). Our purpose is to investigate alterations in downstream effectors, not reported so far in mutated GIST, possibly explaining the primary resistance to targeted treatments. ExperimentalDesign:Two independent naiveGIST cohorts havebeen analyzed forKIT,PDGFRA,KRAS, and BRAF mutations by direct sequencing. Cell lines expressing a constitutively activated and imatinibresponding KIT, alone or in combination with activated KRAS and BRAF, were produced and treated with imatinib. KIT receptor and its downstream effectors were analyzed by direct Western blotting. Results: In naive GISTs carrying activating mutations in KIT or PDGFRA a concomitant activating mutation was detected in KRAS (5%) or BRAF (about 2%) genes. In vitro experiments showed that imatinib was able to switch off the mutated receptor KIT but not the downstream signaling triggered by RAS–RAF