The successful treatment of some tumors, such as gastrointestinal stromal tumors (GISTs), by anti-KIT inhibitors fosters the study of this receptor tyrosine kinase in other malignancies.
We tested the activity of avapritinib, a potent and highly selective inhibitor of mutated KIT and PDGFRA, in three patient-derived xenograft (PDX) GIST models carrying different <i>KIT</i> mutations, with differential sensitivity to standard TKI.<b>Experimental Design:</b> NMRI <i>nu/nu</i> mice (<i>n</i> = 93) were transplanted with human GIST xenografts with <i>KIT</i> exon 11+17 (UZLX-GIST9 <i>
Our results suggest that KIT/PDGFRA mutation is a very common early event in GIST development, that tumour size does not reliably predict the presence of mutation, and that one or more subsequent mutations are required for clinical manifestation.
Immunohistochemical examination showed coexpression of CD117 (c-kit) and CD34 in all independent GISTs and CD117 positivity in mast cells from the skin lesions.
Eight patients with abrupt transition from a classic CD117-positive spindle cell GIST to an anaplastic CD117-negative tumor were investigated for underlying molecular mechanisms of tumor progression.
This homogeneity suggests that the molecular pathogenesis of a GIST results from expansion of a clone that has acquired an activating mutation in KIT without the extreme genetic instability found in the common epithelial cancers.
The introduction of imatinib, an orally administered inhibitor of the KIT receptor tyrosine kinase, is prompting revision of the management algorithms that have traditionally guided the treatment of gastrointestinal stromal tumor (GIST).
Cure can be obtained only by complete surgical removal of the GIST; however, imatinib, an inhibitor of KIT and PDGFRA, is indicated for advanced, recurrent, and/or metastatic GISTs.
Activating mutations of KIT were found in 14 (50%) GISTs, the majority being within exon 11 (n=11; 39.2%), and the other comprised exon 9 AY 502-503 duplications (n=2; 7.2%) and exon 17 Lys --> Aln822 missense mutations (n=1; 3.6%).
Succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (GISTs) constitute a small KIT/PDGFRA-WT GIST subgroup featuring DNA methylation which, although pervasive, appears nevertheless not randomly distributed.
In particular, the responsiveness of GISTs to treatment with the kinase inhibitor imatinib varies substantially depending on the exonic location of the KIT or PDGFRA mutation.
Cas-L overexpression and SRC hyper-activation were also observed in the resistant cells at protein level and they were markedly decreased in KIT siRNA transfected GIST-T1 IR cells.
Ripretinib shows efficacy in preclinical cancer models, and preliminary clinical data provide proof-of-concept that ripretinib inhibits a wide range of KIT mutants in patients with drug-resistant GISTs.
Gain-of-function mutations of the c-kit gene and the expression of phosphorylated KIT are found in most gastrointestinal stromal tumors and mastocytosis.
Additionally, even if the KIT-mutated GISTs alone were considered, a significantly higher expression of PDGFRA could be observed in gastric than in intestinal tumors.
There is growing evidence of phenotype-genotype (KIT, platelet-derived growth factor receptor-alpha, succinate dehydrogenase or other driver gene mutation) and genotype-therapeutic (sensitivity to imatinib) correlations in GIST.
Mutation-activated signaling from the KIT and PDGFRA kinases has been successfully targeted in gastrointestinal stromal tumors (GISTs), with subtle differences between the mutations serving to refine prognosis and more precisely tailor therapy.
Compared with the main GISTs, KIT+ and discovered on GIST 1+ immunostaining features of the spreading lesions were similar in 4 cases, and were weaker or diminished in the other 3 cases.