Activate and resist: L576P-KIT in GIST.

L576P is a rare KIT mutation often reported in cancers other than gastrointestinal stromal tumors (GIST). In GISTs, it correlates with features linked to an aggressive phenotype, eventually resulting in secondary mutations. In vitro findings point out that L576P/KIT is constitutively activated, and shows poor imatinib sensitivity. In this work, histological, immunohistochemical, and biochemical analyses, coupled with mutational-molecular analysis and fluorescence in situ hybridization, were applied to surgical specimens. In parallel, the affinities of wild-type, L576P/KIT, and Delta559/KIT for imatinib were estimated by in silico studies. Despite imatinib treatment and the apparent clinical-imaging response, the detected histological response was very low. KIT resulted, expressed and activated in absence of secondary mutations, BRAF/NRAS mutations, and KIT/PDGFRA gene alterations. Computer modeling proved that L576P/KIT is two times less sensitive than the wild-type counterpart and considerably less affine to imatinib than the sensitive Delta559/KIT. Accordingly, the modeling evidence strongly supports the lack of tumoral regression we observed at the histological level.