Our findings suggest that combinatorial inhibition of CK2 and KIT warrants evaluation as a novel therapeutic strategy in GIST, especially in imatinib-resistant GIST.
This case illustrates that knowing the specific type of KIT mutations may uncover resistance of certain GIST's to TKIs, necessitating more targeted and alternative therapy.
Additional genetic events including RB1, SMARCB1, and MAX except secondary KIT/PDGFRA mutations are the most common for GISTs to evolve into resistant disease.
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>
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.
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.
Furthermore, DEPDC5 modulates the sensitivity of GIST to KIT inhibitors, and the combination therapy with mTOR inhibitor and KIT inhibitor may work better in GIST patients with DEPDC5 inactivation.
The IHC characteristic of GIST in descending order showed positivity for vimentin (88.9%), CD117 (83.3%), CD34 (77.8%), Ki67 (63.9%), SMA (38.9%), desmin (27.8%), and S100 (19.4%).
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 performed RNA sequencing of 75 human GIST tumors from 75 patients, comprising the largest cohort of GISTs sequenced to date, in order to discover differences in the immune infiltrates of KIT and PDGFRA-mutant GIST.
Dedifferentiation in GIST is a rare histologic change which may occur de novo or secondary to imatinib therapy and is characterized by abrupt transition of well-differentiated (WD) GIST to a subclonal anaplastic process that shows loss of immunohistochemical marks (CD117, DOG1).
The pathological findings were compatible with GIST and the tumor consisted of spindle cells with positive staining for KIT, CD34, and DOG1 and negative or weak staining for desmin and S-100 protein.
Discovery of 2-(4-Chloro-3-(trifluoromethyl)phenyl)-<i>N</i>-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)acetamide (CHMFL-KIT-64) as a Novel Orally Available Potent Inhibitor against Broad-Spectrum Mutants of c-KIT Kinase for Gastrointestinal Stromal Tumors.
Taken together, these results demonstrate the existence of a nuclear KIT-driven NFKBIB-RELA-KIT autoregulatory loop in GIST tumorigenesis, which are potential targets for developing combination therapy to overcome imatinib-resistant of KIT-expressing GISTs.
In particular, a discovery cohort (34 GIST with a KIT exon 11 primary mutation, and no toxicity) was analyzed through DMET array that interrogates 1936 variants in 231 genes of the ADME process.