Most gastrointestinal stromal tumours (GIST) are driven by activating oncogenic mutations of KIT/PDGFRA, which provide a compelling therapeutic target.
FGF3/FGF4 duplication was associated with high expression of FGF4, both at mRNA and protein level, a growth factor normally not expressed in adult tissues or in KIT/PDGFRA-mutated GIST.
Gastrointestinal stromal tumor (GIST) is a mesenchymal neoplasm characterized by activating mutations in the related receptor tyrosine kinases KIT and PDGFRA.
Gene expression profiles (GEP) from 31 KIT/PDGFRA-mutant GIST were analyzed to evaluate the tumor microenvironment and immunotherapy predictive signatures such as the expanded IFN-γ-induced immune signature (EIIS) and the T-cell-inflamed signature (TIS).
Through machine learning, we generated gene expression-based immune profiles capable of differentiating KIT and PDGFRA-mutant GISTs, and also identified additional immune features of high PD-1 and PD-L1 expressing tumors across all GIST mutational subtypes, which may provide insight into immunotherapeutic opportunities and limitations in GIST.
The pathogenetically heterogeneous KIT/PDGFRA-WT GISTs were also significantly MGMT-methylated (11/24-46%-, vs. 1/24-4%- of KIT/PDGFRA-mutant cases, p = 0.002).
Succinate dehydrogenase (SDH)-deficient GISTs are wild type and lack KIT proto-oncogene receptor tyrosine kinase and platelet-derived growth factor receptor A ( KIT or PDGFRA) mutations.
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>
Mutually exclusive KIT and PDGFRA mutations are considered to be the earliest events in gastrointestinal stromal tumors (GIST), but insufficient for their malignant progression.
To investigate epigenetic alterations systematically, we mapped DNA methylation, CTCF insulators, enhancers, and chromosome topology in KIT-mutant, PDGFRA-mutant and SDH-deficient GISTs.
Oncogenic KIT or PDGFRA tyrosine kinase mutations are compelling therapeutic targets in most gastrointestinal stromal tumors (GISTs), and the KIT inhibitor, imatinib, is therefore standard of care for patients with metastatic GIST.
The in vivo evidence that PDGFRAp.His845_Asn848delinsPro is sensitive to imatinib was confirmed by the molecular modelling, which may represent a reliable tool for the prediction of clinical outcomes and treatment selection in GIST, especially for rare mutations.
One-third of gastrointestinal stromal tumors (GISTs) that lack KIT or PDGFRA mutations show succinate dehydrogenase (SDH) mutations or promoter hypermethylation.
Gastrointestinal stromal tumors (GISTs) arise anywhere along the gastrointestinal tract, most commonly as a result of c-kit or PDGFRA proto-oncogene mutations.
For patients with PDGFRA D842V mutations, the next generation of drugs may become the first active treatment options.Comprehensive molecular testing of KIT/PDGFRA-wildtype GIST may unmask clinically relevant targets, including NTRK fusions.
Sanger sequencing revealed that the GIST tumor cells contained a deletion mutation (c.2527_2538 del12,843-846del4), which was located in exon 18 of PDGFRA.
Imatinib mesylate (IM), which inhibits both KIT and PDGFRA receptors, significantly improved treatment of advanced (metastatic, recurrent, and/or inoperable) GISTs.